Substituted sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors

ABSTRACT

Selected sulfonylalkanoylamino hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.

This application claims the benefit under 35 U.S.C. 120 of ProvisionalApplication No. 60/006,767 filed Nov. 15, 1995.

BACKGROUND OF THE INVENTION

The present invention relates to retroviral protease inhibitors and,more particularly, relates to novel compounds, composition and methodfor inhibiting retroviral proteases, such as human immunodeficiencyvirus (HIV) protease. This invention, in particular, relates tosulfonylalkanoylamino hydroxyethylamino sulfonamide protease inhibitorcompounds, composition and method for inhibiting retroviral proteases,prophylactically preventing retroviral infection or the spread of aretrovirus, and treatment of a retroviral infection, e.g., an HIVinfection. The subject invention also relates to processes for makingsuch compounds as well as to intermediates useful in such processes.

During the replication cycle of retroviruses, gag and gag-pol genetranscription products are translated as proteins. These proteins aresubsequently processed by a virally encoded protease (or proteinase) toyield viral enzymes and structural proteins of the virus core. Mostcommonly, the gag precursor proteins are processed into the coreproteins and the pol precursor proteins are processed into the viralenzymes, e.g., reverse transcriptase and retroviral protease. It hasbeen shown that correct processing of the precursor proteins by theretroviral protease is necessary for assembly of infectious virons. Forexample, it has been shown that frameshift mutations in the proteaseregion of the pol gene of HIV prevents processing of the gag precursorprotein. It has also been shown through site-directed mutagenesis of anaspartic acid residue in the HIV protease active site that processing ofthe gag precursor protein is prevented. Thus, attempts have been made toinhibit viral replication by inhibiting the action of retroviralproteases.

Retroviral protease inhibition typically involves a transition-statemimetic whereby the retroviral protease is exposed to a mimetic compoundwhich binds (typically in a reversible manner) to the enzyme incompetition with the gag and gag-pol proteins to thereby inhibitspecific processing of structural proteins and the release of retroviralprotease itself. In this manner, retroviral replication proteases can beeffectively inhibited.

Several classes of compounds have been proposed, particularly forinhibition of proteases, such as for inhibition of HIV protease. WO92/08701, WO 93/23368, WO 93/23379, WO 94/04493, WO 94/10136 and WO94/14793 (each of which is incorporated herein by reference in itsentirety) for example describe sulfonylalkanoylamino hydroxyethylamine,sulfonylalkanoylamino hydroxyethylurea, sulfonylalkanoylaminohydroxyethyl sulfonamide and sulfonylalkanoylaminohydroxyethylaminosulfonamide isostere containing retroviral proteaseinhibitors. Other such compounds include hydroxyethylamine isosteres andreduced amide isosteres. See, for example, EP O 346 847; EP O 342,541;Roberts et al, "Rational Design of Peptide-Based Proteinase Inhibitors,"Science, 248, 358 (1990); and Erickson et al, "Design Activity, and 2.8ÅCrystal Structure of a C₂ Symmetric Inhibitor Complexed to HIV-1Protease," Science, 249, 527 (1990). U.S. Pat. No. 5,157,041, WO94/04491, WO 94/04492, WO 94/05639 and U.S. patent application Ser. No.08/294,468, filed Aug. 23, 1994, (each of which is incorporated hereinby reference in its entirety) for example describe hydroxyethylamine,hydroxyethylurea or hydroxyethyl sulfonamide isostere containingretroviral protease inhibitors.

Several classes of compounds are known to be useful as inhibitors of theproteolytic enzyme renin. See, for example, U.S. Pat. No. 4,599,198;U.K. 2,184,730; G.B. 2,209,752; EP O 264 795; G.B. 2,200,115 and U.S.SIR H725. Of these, G.B. 2,200,115, GB 2,209,752, EP O 264,795, U.S. SIRH725 and U.S. Pat. No. 4,599,198 disclose urea-containinghydroxyethylamine renin inhibitors. EP 468 641 discloses renininhibitors and intermediates for the preparation of the inhibitors,which include sulfonamide-containing hydroxyethylamine compounds, suchas3-(t-butoxycarbonyl)amino-cyclohexyl1(phenylsulfonyl)amino-2(5)-butanol.G.B. 2,200,115 also discloses sulfamoyl-containing hydroxyethylaminerenin inhibitors, and EP 0264 795 discloses certainsulfonamide-containing hydroxyethylamine renin inhibitors. However, itis known that, although renin and HIV proteases are both classified asaspartyl proteases, compounds which are effective renin inhibitorsgenerally are not predictive for effective HIV protease inhibition.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to selected retroviral protease inhibitorcompounds, analogs and pharmaceutically acceptable salts, esters andprodrugs thereof. The subject compounds are characterized assulfonylalkanoylamino hydroxyethylamino sulfonamide inhibitor compounds.The invention compounds advantageously inhibit retroviral proteases,such as human immunodeficiency virus (HIV) protease. Therefore, thisinvention also encompasses pharmaceutical compositions, methods forinhibiting retroviral proteases and methods for treatment or prophylaxisof a retroviral infection, such as an HIV infection. The subjectinvention also relates to processes for making such compounds as well asto intermediates useful in such processes.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a retroviralprotease inhibiting compound of the formula: ##STR1## or apharmaceutically acceptable salt, prodrug or ester thereof, wherein nand t each independently represent 0, 1 or 2; preferably n represents 1and t represents 1 or 2;

W represents 0 or S; preferably, W represents O;

R¹ represents hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, --CH₂ CONH₂, --CH₂ CH₂ CONH₂, --CH₂ S(O)₂ NH₂,--CH₂ SCH₃, --CH₂ S(O)CH₃ or --CH₂ S(O)₂ CH₃ radicals; preferably, R¹represents hydrogen, alkyl of 1-5 carbon atoms, alkenyl of 2-5 carbonatoms, alkynyl of 2-5 carbon atoms, hydroxyalkyl of 1-3 carbon atoms,alkoxyalkyl of 1-3 alkyl and 1-3 alkoxy carbon atoms, cyanoalkyl of 1-3alkyl carbon atoms, --CH₂ CONH₂, --CH₂ CH₂ CONH₂, --CH₂ S(O)₂ NH₂, --CH₂SCH₃, --CH₂ S(O)CH₃ or --CH₂ S(O)₂ CH₃ radicals; more preferably, R¹represents hydrogen, alkyl of 1-3 carbon atoms, alkenyl of 2-3 carbonatoms, alkynyl of 2-3 carbon atoms or cyanomethyl radicals; even morepreferably, R¹ represents hydrogen, methyl, ethyl or cyanomethylradicals; yet more preferably, R¹ represents methyl or ethyl radicals;and most preferably, R¹ represents a methyl radical;

R² represents alkyl, aralkyl, alkylthioalkyl, arylthioalkyl orcycloalkylalkyl radicals; preferably, R² represents radicals of alkyl of1-5 carbon atoms, aralkyl of 1-3 alkyl carbon atoms, alkylthioalkyl of1-3 alkyl carbon atoms, arylthioalkyl of 1-3 alkyl carbon atoms orcycloalkylalkyl of 1-3 alkyl carbon atoms and 3-6 ring member carbonatoms; more preferably, R² represents radicals of alkyl of 3-5 carbonatoms, arylmethyl, alkylthioalkyl of 1-3 alkyl carbon atoms,arylthiomethyl or cycloalkylmethyl of 5-6 ring member carbon atomsradicals; even more preferably, R² represents isobutyl, n-butyl, CH₃SCH₂ CH₂ --, benzyl, phenylthiomethyl, (2-naphthylthio)methyl, 4-methoxyphenylmethyl, 4-hydroxyphenylmethyl, 4-fluorophenylmethyl orcyclohexylmethyl radicals; even more preferably, R² represents benzyl,4-fluorophenylmethyl or cyclohexylmethyl radicals; most preferably, R²represents benzyl radical;

R³ represents alkyl, cycloalkyl or cycloalkylalkyl radicals; preferably,R³ represents radicals of alkyl radical of 1-5 carbon atoms, cycloalkylof 5-8 ring members or cycloalkylmethyl radical of 3-6 ring members;more preferably, R³ represents propyl, isoamyl, isobutyl, butyl,cyclopentylmethyl, cyclohexylmethyl, cyclohexyl or cycloheptyl radicals;more preferably R³ represents isobutyl or cyclopentylmethyl radicals;

R⁴ represents aryl, heteroaryl or heterocyclo radicals; preferably, R⁴represents aryl, benzo fused 5 to 6 ring member heteroaryl or benzofused 5 to 6 ring member heterocyclo radicals; or

R⁴ represents a radical of the formula ##STR2## wherein A and B eachindependently represent O, S, SO or SO₂ ; preferably, A and B eachrepresent O;

R⁶ represents deuterium, alkyl or halogen radicals; preferably, R⁶represents deuterium, alkyl of 1-5 carbon atoms, fluoro or chlororadicals; more preferably R⁶ represents deuterium, methyl, ethyl,propyl, isopropyl or fluoro radicals;

R⁷ represents hydrogen, deuterium, alkyl or halogen radicals;preferably, R⁷ represents hydrogen, deuterium, alkyl of 1-3 carbonatoms, fluoro or chloro radicals; more preferably, R⁷ representshydrogen, deuterium, methyl or fluoro radicals; or R⁶ and R⁷ eachindependently represent fluoro or chloro radicals; and preferably, R⁶and R⁷ each represent a fluoro radical; or

R⁴ represents a radical of the formula ##STR3## wherein Z represents O,S or NH; and R⁹ represents a radical of formula ##STR4## wherein Yrepresents O, S or NH; X represents a bond, 0 or NR²¹ ; R²⁰ representsradicals of hydrogen, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl,heterocycloalkyl, aminoalkyl, N-mono-substituted or N,N-disubstitutedaminoalkyl wherein said substituents are alkyl, aralkyl, carboxyalkyl,alkoxycarbonylalkyl, cyanoalkyl or hydroxyalkyl radicals; preferably,R²⁰ represents radicals of hydrogen, alkyl of 1 to 5 carbon atoms,alkenyl of 2 to 5 carbon atoms, alkynyl of 2 to 5 carbon atoms, aralkylof 1 to 5 alkyl carbon atoms, heteroaralkyl of 5 to 6 ring members and 1to 5 alkyl carbon atoms, heterocycloalkyl of 5 to 6 ring members and 1to 5 alkyl carbon atoms, aminoalkyl of 2 to 5 carbon atoms,N-mono-substituted or N,N-disubstituted aminoalkyl of 2 to 5 alkylcarbon atoms wherein said substituents are radicals of alkyl of 1 to 3carbon atoms, aralkyl of 1 to 3 alkyl carbon atoms radicals,carboxyalkyl of 1 to 5 carbon atoms, alkoxycarbonylalkyl of 1 to 5 alkylcarbon atoms, cyanoalkyl of 1 to 5 carbon atoms or hydroxyalkyl of 2 to5 carbon atoms; more preferably, R²⁰ represents radicals of hydrogen,alkyl of 1 to 5 carbon atoms, phenylalkyl of 1 to 3 alkyl carbon atoms,heterocycloalkyl of 5 to 6 ring members and 1 to 3 alkyl carbon atoms,or N-mono-substituted or N,N-disubstituted aminoalkyl of 2 to 3 carbonatoms wherein said substituents are alkyl radicals of 1 to 3 carbonatoms; and most preferably, R²⁰ represents hydrogen, methyl, ethyl,propyl, isopropyl, isobutyl, benzyl, 2-(1-pyrrolidinyl)ethyl,2-(1-piperidinyl)ethyl, 2-(1-piperazinyl)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 2-(4-morpholinyl)ethyl,2-(4-thiomorpholinyl)ethyl or 2-(N,N-dimethylamino)ethyl radicals; or

XR²⁰ represents radicals of hydroxymethyl, aminomethyl,N-mono-substituted or N,N-disubstituted aminomethyl wherein saidsubstituents are alkyl, aralkyl, carboxyalkyl, alkoxycarbonylalkyl,cyanoalkyl or hydroxyalkyl radicals; preferably, XR²⁰ representsradicals of hydroxymethyl, aminomethyl, N-mono-substituted orN,N-disubstituted aminomethyl wherein said substituents are radicals ofalkyl of 1 to 3 carbon atoms, aralkyl of 1 to 3 alkyl carbon atoms,carboxyalkyl of 1 to 5 carbon atoms, alkoxycarbonylalkyl of 1 to 5 alkylcarbon atoms, cyanoalkyl of 1 to 5 carbon atoms or hydroxyalkyl of 2 to5 carbon atoms; more preferably, XR²⁰ represents radicals ofhydroxymethyl, aminomethyl, N-mono-substituted or N,N-disubstitutedaminomethyl wherein said substituents are radicals of alkyl of 1 to 3carbon atoms; and most preferably, XR²⁰ represents hydroxymethyl oraminomethyl radicals;

R²¹ represents hydrogen or alkyl radicals; preferably, R²¹ representshydrogen radical or alkyl radical of 1 to 3 carbon atoms; morepreferably, R²¹ represents hydrogen or methyl radicals; and mostpreferably, R²¹ represents a hydrogen radical; or

the radical of formula --NR²⁰ R²¹ represents a heterocyclo radical;preferably, the radical of formula --NR²⁰ R²¹ represents a 5 to 6 ringmember heterocyclo radical; more preferably, the radical of formula--NR²⁰ R²¹ represents pyrrolidinyl, piperidinyl, piperazinyl,4-methylpiperazinyl, 4-benzylpiperazinyl, morpholinyl or thiomorpholinylradicals; and

R²² represents alkyl or R²⁰ R²¹ N-alkyl radicals; preferably, R²²represents alkyl or R²⁰ R²¹ N-alkyl radicals wherein alkyl is 1 to 3carbon atoms; and more preferably, R²² represents alkyl radical of 1 to3 carbon atoms; and

preferably R⁴ represents phenyl, 2-naphthyl, 4-methoxyphenyl,4-hydroxyphenyl, 3,4-dimethoxyphenyl, 3-aminophenyl, 4-aminophenyl,benzothiazol-5-yl, benzothiazol-6-yl, 2-amino-benzothiazol-5-yl,2-(methoxycarbonylamino)benzothiazol-5-yl, 2-amino-benzothiazol-6-yl,2-(methoxycarbonylamino) benzothiazol-6-yl, 5-benzoxazolyl,6-benzoxazolyl, 6-benzopyranyl, 3,4-dihydrobenzopyran-6-yl,7-benzopyranyl, 3,4-dihydrobenzopyran-7-yl, 2,3-dihydrobenzofuran-5-yl,benzofuran-5-yl, 1,3-benzodioxol-5-yl, 2-methyl-1,3-benzodioxol-5-yl,2,2-dimethyl-1,3-benzodioxol-5-yl, 2,2-dideutero-1,3-benzodioxol-5-yl,2,2-difluoro-1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,5-benzimidazolyl, 2-(methoxycarbonylamino)benzimidazol-5-yl,6-quinolinyl, 7-quinolinyl, 6-isoquinolinyl or 7-isoquinolinyl radicals;more preferably, R⁴ represents phenyl, 2-naphthyl, 4-methoxyphenyl,4-hydroxyphenyl, benzothiazol-5-yl, benzothiazol-6-yl, benzoxazol-5-yl,2,3-dihydrobenzofuran-5-yl, benzofuran-5-yl, 1,3-benzodioxol-5-yl,2-methyl-1,3-benzodioxol-5-yl, 2,2-dimethyl-1,3-benzodioxol-5-yl,2,2-dideutero-1,3-benzodioxol-5-yl, 2,2-difluoro-1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2-(methoxycarbonylamino) benzothiazol-5-yl,2-(methoxycarbonylamino)benzothiazol-6-yl or2-(methoxycarbonylamino)benzimidazol-5-yl radicals; and most preferably,R⁴ represents phenyl, 4-methoxyphenyl, 4-hydroxyphenyl,benzothiazol-5-yl, benzothiazol-6-yl, 2,3-dihydrobenzofuran-5-yl,benzofuran-5-yl, 1,3-benzodioxol-5-yl, 2-methyl-1,3-benzodioxol-5-yl,2,2-dimethyl-1,3-benzodioxol-5-yl, 2,2-dideutero-1,3-benzodioxol-5-yl,2,2-difluoro-1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2-(methoxycarbonylamino)benzothiazol-6-yl or2-(methoxycarbonylamino)benzimidazol-5-yl radicals; and

R⁵ represents heteroaryl or heterocyclo radicals each of which iscoupled via a ring carbon atom; or alkyl radical substituted with R¹⁰,cycloalkylamino, aralkylamino, aminoalkoxycarbonyl,(alkylamino)alkoxycarbonyl, (dialkylamino)alkoxycarbonyl,(aminocarbonyl)(alkoxycarbonyl)methyl or bis(aminocarbonyl)methylradicals, or 1 or more radicals of amino, alkylamino or dialkylamino, or2 or more radicals of hydroxy or alkoxy radicals;

preferably, R⁵ represents 5 to 6 ring member heteroaryl, 5 to 6 ringmember heterocyclo, benzo fused 5 to 6 ring member heteroaryl or benzofused 5 to 6 ring member heterocyclo radicals each of which is coupledvia a ring carbon atom; or alkyl radical of 3-8 carbon atoms substitutedwith 2-5 radicals of hydroxy or alkoxy of 1-3 carbon atoms or 2-3radicals of amino, alkylamino of 1-3 carbon atoms or dialkylamino of 1-3alkyl carbon atoms; or alkyl radical of 1-5 carbon atoms substitutedwith R10; or alkyl radical of 2-4 carbon atoms substituted with radicalsof amino, alkylamino of 1-3 carbon atoms, dialkylamino of 1-3 alkylcarbon atoms, cycloalkylamino of 3-6 ring carbon atoms, aralkylamino of1-3 alkyl carbon atoms, aminoalkoxycarbonyl of 2-5 alkoxy carbon atoms,(alkylamino)alkoxycarbonyl of 1-3 alkyl carbon atoms and 2-5 alkoxycarbon atoms, (dialkylamino)alkoxycarbonyl of 1-3 alkyl carbon atoms andof 2-5 alkoxy carbon atoms, (aminocarbonyl)(alkoxycarbonyl)methyl of 1-3alkoxy carbon atoms or bis(aminocarbonyl)methyl radicals;

more preferably, R⁵ represents a 5 to 6 ring member heteroaryl radicalwhich is coupled via a ring carbon atom, or alkyl radical of 1-5 carbonatoms substituted with R¹⁰, or alkyl radical of 3-8carbon atomssubstituted with 2-5 hydroxy radicals;

R¹⁰ represents heteroaryl, heterocyclo, alkoxycarbonyl, arylcarbonyl,cycloalkylcarbonyl, heteroarylcarbonyl or heterocyclocarbonyl radicals;

preferably, R¹⁰ represents alkoxycarbonyl of 1-5 alkoxy carbon atoms,arylcarbonyl, 3-6 ring membered cycloalkylcarbonyl, benzo fused 3-6 ringmembered cycloalkylcarbonyl, 5 to 6 ring member heteroaryl, 5 to 6 ringmember heterocyclo, benzo fused 5 to 6 ring member heteroaryl, benzofused 5 to 6 ring member heterocyclo, 5 to 6 ring memberheteroarylcarbonyl, 5 to 6 ring member heterocyclocarbonyl, benzo fused5 to 6 ring member heteroarylcarbonyl or benzo fused 5 to 6 ring memberheterocyclocarbonyl radicals;

more preferably, R¹⁰ represents alkoxycarbonyl of 1-4 alkoxy carbonatoms, arylcarbonyl, 5 to 6 ring member heteroaryl, 5 to 6 ring memberheterocyclo, benzo fused 5 to 6 ring member heteroaryl, 5 to 6 ringmember heteroarylcarbonyl or 5 to 6 ring member heterocyclocarbonylradicals;

most preferably, R¹⁰ represents ethoxycarbonyl, tert-butoxycarbonyl,benzoyl, naphthoyl, aminophenylcarbonyl, amidinophenylcarbonyl,pyridylcarbonyl, thiazolylcarbonyl, imidazolylcarbonyl,pyrazolylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl,benzimidazolylcarbonyl, indolylcarbonyl, pyrrolylcarbonyl,quinolinylcarbonyl, pyrrolylcarbonyl, pyrrolidinylcarbonyl,1-(benzyloxycarbonyl)pyrrolidinylcarbonyl, piperidinylcarbonyl,1-(benzyloxycarbonyl)piperidinylcarbonyl, piperazinylcarbonyl,4-methylpiperazinylcarbonyl, 4-benzylpiperazinylcarbonyl,4-(tert-butoxycarbonyl)piperazinylcarbonyl, morpholinylcarbonyl,thiomorpholinylcarbonyl, 1,1-dioxothiomorpholinylcarbonyl, pyrrolidinyl,1-oxopyrrolidin1yl, 1-(benzyloxycarbonyl)pyrrolidinyl, piperidinyl,l-oxopiperidin1yl, piperazinyl, 4-methylpiperazinyl,4-benzylpiperazinyl, 4-(tert-butoxycarbonyl)piperazinyl, morpholinyl,4-oxomorpholin-4-yl, thiomorpholinyl, 1,1-dioxothiomorpholinyl,1,1,4-trioxothiomorpholin-4-yl, thiazolyl, oxazolyl, pyrrolyl, furyl,imidazolyl, pyrazolyl, isoxazolyl, thienyl, pyrimidinyl, pyrazinyl,pyridyl, quinolinyl, quinolonyl, N-methylquinolonyl, benzothiazolyl,benzoxazolyl, benzofuranyl, benzimidazolyl, indolyl,dihydroxytetrahydrofuran-5-yl, trihydroxytetrahydrofuran-5-yl,2-methoxydihydroxytetrahydrofuran-5-yl, trihydroxytetrahydrofuranyl,2-(hydroxymethyl)dihydroxytetrahydrofuran-5-yl,2-methoxytrihydroxytetrahydropyran-6-yl ortetrahydroxytetrahydropyran-6-yl radicals; or

R¹⁰ represents R¹¹ R¹² N--C(O)--radical, wherein

R¹¹ represents heteroaryl, heterocyclo, heteroaralkyl, heterocycloalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkylaminoalkyl,aralkylaminoalkyl or diaminoalkyl radicals; preferably, R¹¹ represents 5to 6 ring member heteroaryl, 5 to 6 ring member heterocyclo, benzo fused5 to 6 ring member heteroaryl or benzo fused 5 to 6 ring memberheterocyclo radicals, or alkyl radical of 1-5 carbon atoms substitutedwith 5 to 6 ring member heteroaryl, 5 to 6 ring member heterocyclo,benzo fused 5 to 6 ring member heteroaryl or benzo fused 5 to 6 ringmember heterocyclo radicals, or alkyl radical of 2-4 carbon atomssubstituted with radicals of amino, alkylamino of 1-3 carbon atoms,dialkylamino of 1-3 alkyl carbon atoms, cycloalkylamino of 3-6 ringcarbon atoms or aralkylamino of 1-3 alkyl carbon atoms, or diaminoalkylradical of 3-5 carbon atoms; more preferably, R¹¹ represents alkylradical of 1-3 carbon atoms substituted with 5 to 6 ring memberheteroaryl or 5 to 6 ring member heterocyclo radicals; even morepreferably, R¹¹ represents alkyl radical of 1-3 carbon atoms substitutedwith pyrrolidinyl, 1-oxopyrrolidin-1-yl, piperidinyl,1-oxopiperidin-1-yl, piperazinyl, 4-methylpiperazinyl,4-benzylpiperazinyl, 4-(tert-butoxycarbonyl)piperazinyl, morpholinyl,4-oxomorpholin-4-yl, thiomorpholinyl, 1,1-dioxothiomorpholinyl or1,1,4-trioxothiomorpholin-4-yl radicals; most preferably, R¹¹ represents2-pyrrolidinylmethyl, 2-(1-pyrrolidinyl)ethyl,2-(1-oxopyrrolidin-1-yl)ethyl, 2-(1-piperidinyl)ethyl,2-(1-oxopiperidin-1-yl)ethyl, 2-(4-morpholinyl)ethyl,2-(4-oxomorpholin-4-yl)ethyl, 2-(4-thiomorpholinyl)ethyl,2-(1,1-dioxothiomorpholin-4-yl)ethyl,2-(1,1,4-trioxothiomorpholin-4-yl)ethyl or 1,3-diaminoprop-2-ylradicals; and

R¹² represents hydrogen or alkyl radicals; preferably, R¹² representsradicals of hydrogen or alkyl of 1-3 carbon atoms; more preferably, R¹²represents hydrogen or methyl radicals; most preferably, R¹² representsa hydrogen radical;

more preferably, R⁵ represents 2-pyridyl, ethoxycarbonylpropyl,benzoylmethyl, morpholinylcarbonylmethyl,4-(tert-butoxycarbonyl)piperazinylcarbonylmethyl,piperazinylcarbonylmethyl,4-(tert-butoxycarbonyl)piperazinylcarbonylethyl,piperazinylcarbonylethyl, thiomorpholinylcarbonylmethyl,1,1-dioxothiomorpholinylcarbonylmethyl, imidazolylethyl,imidazolylcarbonylmethyl, pyrazolylethyl, thiazolylethyl,imidazolylmethyl, pyrazolylmethyl, thiazolylmethyl,benzimidazolylmethyl, pyridylethyl, pyridylcarbonylmethyl,pyrrolidinylmethyl, 1-(benzyloxycarbonyl)pyrrolidinylmethyl,5-methoxy-3,4-dihydroxy-tetrahydrofuranylmethyl, N-2-(4-oxomorpholin-4-yl)ethyl!aminocarbonylmethyl, N-2-(1-pyrrolidinyl)ethyl!aminocarbonylmethyl, N-2-(1-pyrrolidinyl)ethyl!aminocarbonylethyl, N-2-(1-oxopyrrolidin-1-yl)ethyl!aminocarbonylmethyl,2,2-bis(hydroxymethyl)ethyl, 2,2,2-tris(hydroxymethyl)ethyl, 2-(2-aminoethyl)aminocarbonyl!ethyl or 2-(2-(methylamino)ethyl)aminocarbonyl!ethyl radicals; and most preferably,R⁵ represents benzoylmethyl,4-(tert-butoxycarbonyl)piperazinylcarbonylmethyl,4-(tert-butoxycarbonyl)piperazinylcarbonylethyl,piperazinylcarbonylethyl, imidazolylethyl, pyrazolylethyl,thiazolylethyl, imidazolylmethyl, pyrazolylmethyl, thiazolylmethyl,pyridylethyl, pyridylcarbonylmethyl, pyrrolidinylmethyl or1-(benzyloxycarbonyl)pyrrolidinylmethyl radicals.

Preferably, the absolute stereochemistry of the carbon atom of--CH(OH)--group is (R) and the absolute stereochemistry of the carbonatoms of --CH(R¹)--and --CH(R²)--groups is (S).

A family of compounds of particular interest within Formula I arecompounds embraced by the formula ##STR5## or a pharmaceuticallyacceptable salt, prodrug or ester thereof, wherein t, R¹, R², R³, R⁴ andR⁵ are as defined above.

A family of compounds of further interest within Formula II arecompounds embraced by the formula ##STR6## or a pharmaceuticallyacceptable salt, prodrug or ester thereof, wherein t, R¹, R² ₁ R³, R⁴and R⁵ are as defined above.

Compounds of interest include the following:

N- 2R-hydroxy-3 (2-methylpropyl) (1, 3-benzodioxol-5-yl) sulfonyl!amino!-1S-(phenylmethyl)propyl! -2S-methyl-3- (2-pyridylcarbonylmethyl)sulfonyl propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyridylcarbonylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyridylcarbonylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl)((benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyridylcarbonylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyridylcarbonylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyridylcarbonylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyridylcarbonylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyridylcarbonylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyridylcarbonylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-((3-pyridylcarbonylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)

sulfonyllamino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(4-pyridylcarbonylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(4-pyridylcarbonylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(4-pyridylcarbonylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(4-pyridylcarbonylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(4-pyridylcarbonylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyrazolylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyllamino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyrazolylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyrazolylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyrazolylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyrazolylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(benzoylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(benzoylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(benzoylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(benzoylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(benzoylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(5-thiazolylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(5-thiazolylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(5-thiazolylmethyl)sulfonylipropanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(5-thiazolylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyllamino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(5-thiazolylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-2-ylethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyll-2S-methyl-3-(2-pyrid-2-ylethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-2-ylethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-2-ylethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-2-ylethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl)!-2S-methyl-3-(2-pyrid-3-ylethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-3-ylethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-3-ylethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-3-ylethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-3-ylethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyllamino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-4-ylethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-4-ylethyl)sulfonyllpropanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-4-ylethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyllamino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-4-ylethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-4-ylethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(1-(benzyloxycarbonyl)pyrrolidin-2S-ylmethyl)sulfonyl! propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(1-(benzyloxycarbonyl)pyrrolidin-2S-ylmethyl)sulfonyl! propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(1-(benzyloxycarbonyl)pyrrolidin-2S-ylmethyl)sulfonyl! propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(1-(benzyloxycarbonyl)pyrrolidin-2S-ylmethyl)sulfonyl! propanamide;

N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(1-(benzyloxycarbonyl)pyrrolidin-2S-ylmethyl)sulfonyl! propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(1-piperazinylcarbonyl)ethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl) sulfonyl!amino!-1S- (phenylmethyl)propyl! -2S-methyl-3-(2-(1-piperazinylcarbonyl)ethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(1-piperazinylcarbonyl)ethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(1-piperazinylcarbonyl)ethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(1-piperazinylcarbonyl)ethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(2-aminoethylaminocarbonyl)ethyl)sulfonyllpropanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(2-aminoethylaminocarbonyl)ethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3-((2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(2-aminoethylaminocarbonyl)ethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(2-aminoethylaminocarbonyl)ethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyllamino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(2-aminoethylaminocarbonyl)ethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (i,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-2-(hydroxymethyl)-3-hydroxypropyl!sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-2-(hydroxymethyl)-3-hydroxypropyl!sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-2-(hydroxymethyl)-3-hydroxypropyl!sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-2-(hydroxymethyl)-3-hydroxypropyl!sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-2-(hydroxymethyl)-3-hydroxypropyl!sulfonyl! propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(pyrrolidin-2R-ylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-((pyrrolidin-2R-ylmethyl)sulfonylipropanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(pyrrolidin-2R-ylmethyl)sulfonyl!propanamide;

N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyllamino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(pyrrolidin-2R-ylmethyl)sulfonyl!propanamide; and

N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(pyrrolidin-2R-ylmethyl)sulfonyl!propanamide.

As utilized herein, the term "alkyl", alone or in combination, means astraight-chain or branched-chain alkyl radical containing preferablyfrom 1 to 8 carbon atoms, more preferably from 1 to 5 carbon atoms, mostpreferably 1-3 carbon atoms. Examples of such radicals include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,pentyl, iso-amyl, hexyl, octyl and the like. The term "hydroxyalkyl",alone or in combination, means an alkyl radical as defined above whereinat least one hydrogen radical is replaced with a hydroxyl radical,preferably 1-3 hydrogen radicals are replaced by hydroxyl radicals, morepreferably, 1-2 hydrogen radicals are replaced by hydroxyl radicals, andmost preferably, one hydrogen radical is replaced by a hydroxyl radical.The term "alkenyl", alone or in combination, means a straight-chain orbranched-chain hydrocarbon radical having one or more double bonds andcontaining preferably from 2 to 8 carbon atoms, more preferably from 2to 5 carbon atoms, most preferably from 2 to 3 carbon atoms. Examples ofsuitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl,1,4-butadienyl and the like. The term "alkynyl", alone or incombination, means a straight-chain or branched chain hydrocarbonradical having one or more triple bonds and containing preferably from 2to 8 carbon atoms, more preferably from 2 to 5 carbon atoms, mostpreferably from 2 to 3 carbon atoms. Examples of alkynyl radicalsinclude ethynyl, propynyl (propargyl), butynyl and the like. The term"alkoxy", alone or in combination, means an alkyl ether radical whereinthe term alkyl is as defined above. Examples of suitable alkyl etherradicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy and the like. The term "cycloalkyl",alone or in combination, means a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl radical wherein each cyclicmoiety contains preferably from 3 to 8 carbon atom ring members, morepreferably from 3 to 7 carbon atom ring members, most preferably from 5to 6 carbon atom ring members, and which may optionally be a benzo fusedring system which is optionally substituted as defined herein withrespect to the definition of aryl. Examples of such cycloalkyl radicalsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like."Bicyclic" and "tricyclic" as used herein are intended to include bothfused ring systems, such as naphthyl and β-carbolinyl, and substitutedring systems, such as biphenyl, phenylpyridyl, naphthyl anddiphenylpiperazinyl. The term "cycloalkylalkyl" means an alkyl radicalas defined above which is substituted by a cycloalkyl radical as definedabove. Examples of such cycloalkylalkyl radicals includecyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl,2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl,cyclopentylpropyl, cyclohexylbutyl and the like. The term "benzo", aloneor in combination, means the divalent radical C6H₄ ═derived frombenzene. The term "aryl", alone or in combination, means a phenyl ornaphthyl radical which is optionally substituted with one or moresubstituents selected from alkyl, alkoxy, halogen, hydroxy, amino,nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl,heterocyclo, alkanoylamino, amido, amidino, alkoxycarbonylamino,N-alkylamidino, alkylamino, dialkylamino, N-alkylamido,N,N-dialkylamido, aralkoxycarbonylamino, alkylthio, alkylsulfinyl,alkylsulfonyl and the like. Examples of aryl radicals are phenyl,p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl,3-methyl-4-methoxyphenyl, 4-CF₃ -phenyl, 4-fluorophenyl, 4-chlorophenyl,3-nitrophenyl, 3-aminophenyl, 3-acetamidophenyl, 4-acetamidophenyl,2-methyl-3-acetamidophenyl, 2-methyl-3-aminophenyl,3-methyl-4-aminophenyl, 2-amino-3-methylphenyl,2,4-dimethyl-3-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl,1-naphthyl, 2-naphthyl, 3-amino-1-naphthyl, 2-methyl-3-amino1naphthyl,6-amino-2-naphthyl, 4,6-dimethoxy-2-naphthyl, piperazinylphenyl and thelike. The terms "aralkylll and "aralkoxy", alone or in combination,means an alkyl or alkoxy radical as defined above in which at least onehydrogen atom is replaced by an aryl radical as defined above, such asbenzyl, benzyloxy, 2-phenylethyl, dibenzylmethyl, hydroxyphenylmethyl,methylphenylmethyl, diphenylmethyl, diphenylmethoxy,4-methoxyphenylmethoxy and the like. The term "aralkoxycarbonyl", aloneor in combination, means a radical of the formula aralkyl--O--C(O)--inwhich the term "aralkyll", has the significance given above. Examples ofan aralkoxycarbonyl radical are benzyloxycarbonyl and4-methoxyphenylmethoxycarbonyl. The term "aryloxyll" means a radical ofthe formula aryl-O--in which the term aryl has the significance given.above. The term "alkanoyl", alone or in combination, means an acylradical derived from an alkanecarboxylic acid, examples of which includeacetyl, propionyl, butyryl, valeryl, 4-methylyaleryl, and the like. Theterm "cycloalkylcarbonyl" means an acyl radical of the formulacycloalkyl- C(O)--in which the term "cycloalkyl" has the significancegive above, such as cyclopropylcarbonyl, cyclohexylcarbonyl,adamantylcarbonyl, 1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl,l-hydroxy-1,2,3,4-tetrahydro-6-naphthoyl and the like. The term"aralkanoyl" means an acyl radical derived from an aryl-substitutedalkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl,and the like. The term "aroyl" means an acyl radical derived from anarylcarboxylic acid, "aryl", having the meaning given above. Examples ofsuch aroyl radicals include substituted and unsubstituted benzoyl ornapthoyl such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.The term "heteroatoms" means nitrogen, oxygen and sulfur heteroatoms.The terms "heterocyclo," alone or in combination, means a saturated orpartially unsaturated monocyclic, bicyclic or tricyclic heterocycleradical containing at least one, preferably 1 to 4, more preferably 1 to2, nitrogen, oxygen or sulfur atom ring member and having preferably 3to 8 ring members in each ring, more preferably 3 to 7 ring members ineach ring and most preferably 5 to 6 ring members in each ring."Heterocyclo" is intended to include sulfones, sulfoxides, N-oxides oftertiary nitrogen ring members, and carbocyclic fused and benzo fusedring systems. Such heterocyclo radicals may be optionally substituted onat least one, preferably 1 to 4, more preferably 1 to 3, most preferably1 to 2, carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, aryl,aralkyl, heteroaryl, heteroaralkyl, amidino, N-alkylamidino,alkoxycarbonylamino, alkylsulfonylamino and the like, and/or on asecondary nitrogen atom (i.e., --NH--) by hydroxy, alkyl,aralkoxycarbonyl, alkanoyl, alkoxycarbonyl, heteroaralkyl, phenyl orphenylalkyl and/or on a tertiary nitrogen atom (i.e., ═N--) by oxido."Heterocycloalkyl" means an alkyl radical as defined above in which atleast one hydrogen atom is replaced by a heterocyclo radical as definedabove, such as pyrrolidinylmethyl, tetrahydrothienylmethyl,pyridylmethyl and the like. The term "heteroaryl", alone or incombination, means an aromatic heterocyclo radical as defined above,which is optionally substituted as defined above with respect to thedefinitions of aryl and heterocyclo. Examples of such heterocyclo andheteroaryl groups are pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol 4-yl,1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl, pyridyl, (e.g.,2-(l-piperidinyl)pyridyl and 2-(4-benzyl piperazin1yl1pyridinyl, etc.),pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl,tetrahydrothienyl and its sulfoxide and sulfone derivatives, triazolyl,oxazolyl, thiazolyl, indolyl (e.g., 2-indolyl, etc.), quinolinyl, (e.g.,2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, quinolin-2-onyl,etc.), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, etc.),tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydro-2-quinolyl, etc.),1,2,3,4-tetrahydroisoquinolinyl (e.g.,1,2,3,4-tetrahydro1oxo-isoquinolinyl, etc.), quinoxalinyl, β-carbolinyl,2-benzofurancarbonyl, 1-,2-,4- or 5-benzimidazolyl,methylenedioxyphen-4-yl, methylenedioxyphen-5-yl, ethylenedioxyphenyl,benzothiazolyl, benzopyranyl, benzofuryl, 2,3-dihydrobenzofuryl,benzoxazolyl and the like. The term "heteroaralkyl", alone or incombination, means an alkyl radical as defined above in which at leastone hydrogen atom is replaced by an heteroaryl radical as defined above,such as benzofurylmethyl, 3-furylpropyl, quinolinylmethyl,2-thienylethyl, pyridylmethyl, 2-pyrrolylpropyl, 1-imidazolylethyl andthe like. The term "cycloalkylalkoxycarbonyll", means an acyl groupderived from a cycloalkylalkoxycarboxylic acid of the formulacycloalkylalkyl-O--COOH wherein cycloalkylalkyl has the meaning givenabove. The term "aryloxyalkanoyll", means an acyl radical of the formulaaryl-O-alkanoyl wherein aryl and alkanoyl have the meaning given above.The term "heterocycloalkoxycarbonyl" means an acyl group derived fromheterocycloalkyl-O--COOH wherein heterocycloalkyl is as defined above.The term "heterocycloalkanoyl" is an acyl radical derived from aheterocycloalkylcarboxylic acid wherein heterocyclo has the meaninggiven above. The term "heterocycloalkoxycarbonyl" means an acyl radicalderived from a heterocycloalkyl-O--COOH wherein heterocyclo has themeaning given above. The term heteroaryloxycarbonyl" means an acylradical derived from a carboxylic acid represented by heteroaryl-O--COOHwherein heteroaryl has the meaning given above. The term "aminocarbonyl"alone or in combination, means an amino-substituted carbonyl (carbamoyl)group wherein the amino group can be a primary, secondary or tertiaryamino group containing substituents selected from alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl radicals and the like. The term"aminoalkanoyl" means an acyl group derived from an amino-substitutedalkylcarboxylic acid wherein the amino group can be a primary, secondaryor tertiary amino group containing substituents selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like. Theterm "halogen" means fluorine, chlorine, bromine or iodine. The term"haloalkyl" means an alkyl radical having the meaning as defined abovewherein one or more hydrogens are replaced with a halogen. Examples ofsuch haloalkyl radicals include chloromethyl, 1-bromoethyl,fluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl andthe like. The term "leaving group" (L or W) generally refers to groupsreadily displaceable by a nucleophile, such as an amine, a thiol or analcohol nucleophile. Such leaving groups are well known in the art.Examples of such leaving groups include, but are not limited to,N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates,tosylates and the like. Preferred leaving groups are indicated hereinwhere appropriate.

Procedures for preparing the compounds of Formula I are set forth below.It should be noted that the general procedure is shown as it relates topreparation of compounds having the specified stereochemistry, forexample, wherein the absolute stereochemistry about the hydroxyl groupis designated as (R). However, such procedures are generally applicableto those compounds of opposite configuration, e.g., where thestereochemistry about the hydroxyl group is (S). In addition, thecompounds having the (R) stereochemistry can be utilized to producethose having the (S) stereochemistry. For example, a compound having the(R) stereochemistry can be inverted to the (S) stereochemistry usingwell-known methods.

Preparation of Compounds of Formula I

The compounds of the present invention represented by Formula I abovecan be prepared utilizing the following general procedures asschematically shown in Schemes I and II. ##STR7##

An N-protected chloroketone derivative of an amino acid having theformula: ##STR8## wherein P represents an amino protecting group, and R²is as defined above, is reduced to the corresponding alcohol utilizingan appropriate reducing agent. Suitable amino protecting groups are wellknown in the art and include carbobenzoxy, t-butoxycarbonyl, and thelike. A preferred amino protecting group is carbobenzoxy. A preferredN-protected chloroketone is N-benzyloxycarbonyl-L-phenylalaninechloromethyl ketone. A preferred reducing agent is sodium borohydride.The reduction reaction is conducted at a temperature of from -10° C. toabout 25 °C., preferably at about 0° C., in a suitable solvent systemsuch as, for example, tetrahydrofuran, and the like. The N-protectedchloroketones are commercially available, e.g., such as from Bachem,Inc., Torrance, California. Alternatively, the chloroketones can beprepared by the procedure set forth in S. J. Fittkau, J. Prakt. Chem.,315, 1037 (1973), and subsequently N-protected utilizing procedureswhich are well known in the art.

The halo alcohol can be utilized directly, as described below, or,preferably, is reacted, preferably at room temperature, with a suitablebase in a suitable solvent system to produce an N-protected aminoepoxide of the formula: ##STR9## wherein P and R² are as defined above.Suitable solvent systems for preparing the amino epoxide includeethanol, methanol, isopropanol, tetrahydrofuran, dioxane, and the likeincluding mixtures thereof. Suitable bases for producing the epoxidefrom the reduced chloroketone include potassium hydroxide, sodiumhydroxide, potassium t-butoxide, DBU and the like. A preferred base ispotassium hydroxide.

Alternatively, a protected amino epoxide can be prepared, such as inco-owned and co-pending PCT patent application Ser. No. PCT/US93/04804(WO 93/23388) and PCT/US94/12201, and U.S. patent application AttorneyDocket No. C-2860, each of which is incorporated herein by reference intheir entirety) disclose methods of preparing chiral epoxide, chiralcyanohydrin, chiral amine and other chiral intermediates useful in thepreparation of retroviral protease inhibitors, starting with a DL-, D-or L-amino acid which is reacted with a suitable amino-protecting groupin a suitable solvent to produce an amino-protected amino acid ester.For the purposes of illustration, a protected L-amino acid with thefollowing formula will be used to prepare the inhibitors of thisinvention: ##STR10## wherein P3 represents carboxyl-protecting group,e.g., methyl, ethyl, benzyl, tertiary-butyl, 4-methoxyphenylmethyl andthe like; R² is as defined above; and p¹ and p² independently areselected from amine protecting groups, including but not limited to,aralkyl, substituted aralkyl, cycloalkenylalkyl and substitutedcycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl,aralkoxycarbonyl and silyl. Examples of aralkyl include, but are notlimited to benzyl, ortho-methylbenzyl, trityl and benzhydryl, which canbe optionally substituted with halogen, alkyl of C1-C8, alkoxy, hydroxy,nitro, alkylene, amino, alkylamino, acylamino and acyl, or their salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthalenyl, indanyl, anthracenyl, durenyl,9-(9-phenylfluorenyl) and phenanthrenyl, cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals containing cycloalkyls ofC6-C10. Suitable acyl groups include carbobenzoxy, t-butoxycarbonyl,iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl,tri-fluoroacetyl, tri-chloroacetyl, phthaloyl and the like. Preferablyp¹ and p² are independently selected from aralkyl and substitutedaralkyl. More preferably, each of p¹ and p² is benzyl.

Additionally, the p¹ and/or p² protecting groups can form a heterocyclicring with the nitrogen to which they are attached, for example,1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl andthe like and where these heterocyclic groups can further includeadjoining aryl and cycloalkyl rings. In addition, the heterocyclicgroups can be mono-, di- or tri-substituted, e.g., nitrophthalimidyl.The term silyl refers to a silicon atom optionally substituted by one ormore alkyl, aryl and aralkyl groups.

Suitable silyl protecting groups include, but are not limited to,trimethylsilyl, triethylsilyl, tri-isopropylsilyl,tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of the amine functions to provide mono-or bis-disilylamine can provide derivatives of the aminoalcohol, aminoacid, amino acid esters and amino acid amide. In the case of aminoacids, amino acid esters and amino acid amides, reduction of thecarbonyl function provides the required mono- or bis-silyl aminoalcohol.Silylation of the aminoalcohol can lead to the N,N,O-tri-silylderivative. Removal of the silyl function from the silyl ether functionis readily accomplished by treatment with, for example, a metalhydroxide or ammonium flouride reagent, either as a discrete reactionstep or in situ during the preparation of the amino aldehyde reagent.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chlorie,diphenylmethylsilyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

The amino-protected L-amino acid ester is then reduced, to thecorresponding alcohol. For example, the amino-protected L-amino acidester can be reduced with diisobutylaluminum hydride at -78° C. in asuitable solvent such as toluene. Preferred reducing agents includelithium aluminium hydride, lithium borohydride, sodium borohydride,borane, lithium tri-ter-butoxyaluminum hydride, borane/THF complex. Mostpreferably, the reducing agent is diisobutylaluminum hydride (DiBAL-H)in toluene. The resulting alcohol is then converted, for example, by wayof a Swern oxidation, to the corresponding aldehyde of the formula:##STR11## wherein p¹ , p² and R² are as defined above. Thus, adichloromethane solution of the alcohol is added to a cooled (-75 °to-68° C.) solution of oxalyl chloride in dichloromethane and DMSO indichloromethane and stirred for 35 minutes.

Acceptable oxidizing reagents include, for example, sulfurtrioxide-pyridine complex and DMSO, oxalyl chloride and DMSO, acetylchloride or anhydride and DMSO, trifluoroacetyl chloride or anhydrideand DMSO, methanesulfonyl chloride and DMSO or tetrahydrothiophene-S-oxide, toluenesulfonyl bromide and DMSO,trifluoromethanesulfonyl anhydride (triflic anhydride) and DMSO,phosphorus pentachloride and DMSO, dimethylphosphoryl chloride and DMSOand isobutyl chloroformate and DMSO. The oxidation conditions reportedby Reetz et al (Angew Chem., 99, p. 1186, (1987)!, Anaew Chem. Int. Ed.Engl., 26, p. 1141, 1987) employed oxalyl chloride and DMSO at -78° C.

The preferred oxidation method described in this invention is sulfurtrioxide pyridine complex, triethylamine and DMSO at room temperature.This system provides excellent yields of the desired chiral protectedamino aldehyde usable without the need for purification i.e., the needto purify kilograms of intermediates by chromatography is eliminated andlarge scale operations are made less hazardous. Reaction at roomtemperature also eliminated the need for the use of low temperaturereactor which makes the process more suitable for commercial production.

The reaction may be carried out under an inert atmosphere such asnitrogen or argon, or normal or dry air, under atmospheric pressure orin a sealed reaction vessel under positive pressure. Preferred is anitrogen atmosphere. Alternative amine bases include, for example,tri-butyl amine, tri-isopropyl amine, N-methylpiperidine, N-methylmorpholine, azabicyclononane, diisopropylethylamine,2,2,6,6-tetramethylpiperidine, N,N-dimethylaminopyridine, or mixtures ofthese bases. Triethylamine is a preferred base. Alternatives to pureDMSO as solvent include mixtures of DMSO with non-protic or halogenatedsolvents such as tetrahydrofuran, ethyl acetate, toluene, xylene,dichloromethane, ethylene dichloride and the like. Dipolar aproticco-solvents include acetonitrile, dimethylformamide, dimethylacetamide,acetamide, tetramethyl urea and its cyclic analog, N-methylpyrrolidone,sulfolane and the like. Rather than N,N-dibenzylphenylalaninol as thealdehyde precursor, the phenylalaninol derivatives discussed above canbe used to provide the corresponding N-monosubstituted either p¹ or p²=H! or N,N-disubstituted aldehyde.

In addition, hydride reduction of an amide or ester derivative of thecorresponding benzyl (or other suitable protecting group) nitrogenprotected phenylalanine, substituted phenylalanine or cycloalkyl analogof phenylalanine derivative can be carried out to provide the aldehydes.Hydride transfer is an additional method of aldehyde synthesis underconditions where aldehyde condensations are avoided, cf, OppenauerOxidation.

The aldehydes of this process can also be prepared by methods ofreducing protected phenylalanine and phenylalanine analogs or theiramide or ester derivatives by, e.g., sodium amalgam with HCl in ethanolor lithium or sodium or potassium or calcium in ammonia. The reactiontemperature may be from about -20° C. to about 45° C., and preferablyfrom abut 5° C. to about 25° C. Two additional methods of obtaining thenitrogen protected aldehyde include oxidation of the correspondingalcohol with bleach in the presence of a catalytic amount of2,2,6,6-tetramethyl1pyridyloxy free radical. In a second method,oxidation of the alcohol to the aldehyde is accomplished by a-catalyticamount of tetrapropylammonium perruthenate in the presence ofN-methylmorpholine-N-oxide.

Alternatively, an acid chloride derivative of a protected phenylalanineor phenylalanine derivative as disclosed above can be reduced withhydrogen and a catalyst such as Pd on barium carbonate or bariumsulphate, with or without an additional catalyst moderating agent suchas sulfur or a thiol (Rosenmund Reduction).

The aldehyde resulting from the Swern oxidation is then reacted with ahalomethyllithium reagent, which reagent is generated in situ byreacting an alkyllithium or arylithium compound with a dihalomethanerepresented by the formula X¹ CH₂ X² wherein X¹ and X² independentlyrepresent I, Br or Cl. For example, a solution of the aldehyde andchloroiodomethane in THF is cooled to -78° C. and a solution ofn-butyllithium in hexane is added. The resulting product is a mixture ofdiastereomers of the corresponding amino-protected epoxides of theformulas: ##STR12## The diastereomers can be separated e.g., bychromatography, or, alternatively, once reacted in subsequent steps thediastereomeric products can be separated. A D-amino acid can be utilizedin place of the L-amino acid in order to prepare compounds having an (S)stereochemistry at the carbon bonded to R².

The addition of chloromethylithium or bromomethylithium to a chiralamino aldehyde is highly diastereoselective. Preferably, thechloromethyllithium or bromomethylithium is generated in-situ from thereaction of the dihalomethane and n-butyllithium. Acceptablemethyleneating halomet-hanes include chloroiodomethane,bromochloromethane, dibromomethane, diiodomethane, bromofluoromethaneand the like. The sulfonate ester of the addition product of, forexample, hydrogen bromide to formaldehyde is also a methyleneatingagent. Tetrahydrofuran is the preferred solvent, however alternativesolvents such as toluene, dimethoxyethane, ethylene dichloride,methylene chloride can be used as pure solvents or as a mixture. Dipolaraprotic solvents such as acetonitrile, DMF, N-methylpyrrolidone areuseful as solvents or as part of a solvent mixture. The reaction can becarried out under an inert atmosphere such as nitrogen or argon. Forn-butyl lithium can be substituted other organometalic reagents reagentssuch as methyllithium, tert-butyl lithium, sec-butyl lithium,phenyllithium, phenyl sodium and the like. The reaction can be carriedout at temperatures of between about -80° C. to 0° C. but preferablybetween about -80° C. to -20° C. The most preferred reactiontemperatures are between -40° C. to -15° C. Reagents can be singly butmultiple 40 additions are preferred in certain conditions. The preferredpressure of the reaction is atmospheric however a positive pressure isvaluable under certain conditions such as a high humidity environment.

Alternative methods of conversion to the epoxides of this inventioninclude substitution of other charged methylenation precurser speciesfollowed by their treatment with base to form the analogous anion.Examples of these species include trimethylsulfoxonium tosylate ortriflate, tetramethylammonium halide, methyldiphenylsulfoxonium halidewherein halide is chloride, bromide or iodide.

The conversion of the aldehydes of this invention into their epoxidederivative can also be carried out in multiple steps. For example, theaddition of the anion of thioanisole prepared from, for example, a butylor aryl lithium reagent, to the protected aminoaldehyde, oxidation ofthe resulting protected aminosulfide alcohol with well known oxidizingagents such as hydrogen peroxide, tert-butyl hypochlorite, bleach orsodium periodate to give a sulfoxide. Alkylation of the sulfoxide with,for example, methyl iodide or bromide, methyl tosylate, methyl mesylate,methyl triflate, ethyl bromide, isopropyl bromide, benzyl chloride orthe like, in the presence of an organic or inorganic base Alternatively,the protected aminosulfide alcohol can be alkylated with, for example,the alkylating agents above, to provide sulfonium salts that aresubsequently converted into the subject epoxides with tert-amine ormineral bases.

The desired epoxides formed, using most preferred conditions,diastereoselectively in ratio amounts of at least about an 85:15 ratio(S:R). The product can be purified by chromatography to give thediastereomerically and enantiomerically pure product but it is moreconveniently used directly without purification to prepare retroviralprotease inhibitors. The foregoing process is applicable to mixtures ofoptical isomers as well as resolved compounds. If a particular opticalisomer is desired, it can be selected by the choice of startingmaterial, e.g., L-phenylalanine, D-phenylalanine, L-phenylalaninol,D-phenylalaninol, D-hexahydrophenylalaninol and the like, or resolutioncan occur at intermediate or final steps. Chiral auxiliaries such as oneor two equivilants of camphor sulfonic acid, citric acid, camphoricacid, 2-methoxyphenylacetic acid and the like can be used to form salts,esters or amides of the compounds of this invention. These compounds orderivatives can be crystallized or separated chromatographically usingeither a chiral or achiral column as is well known to those skilled inthe art.

The amino epoxide is then reacted, in a suitable solvent system, with anequal amount, or preferably an excess of, a desired amine of the formulaR³ NH₂, wherein R³ is hydrogen or is as defined above. The reaction canbe conducted over a wide range of temperatures, e.g., from about 10° C.to about 100° C., but is preferably, but not necessarily, conducted at atemperature at which the solvent begins to reflux. Suitable solventsystems include protic, non-protic and dipolar aprotic organic solventssuch as, for example, those wherein the solvent is an alcohol, such asmethanol, ethanol, isopropanol, and the like, ethers such astetrahydrofuran, dioxane and the like, and toluene,N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. Apreferred solvent is isopropanol. The resulting product is a3-(N-protected amino)-3-(R²)-1-(NHR³)-propan-2-ol derivative(hereinafter referred to as an amino alcohol) can be represented by theformulas: ##STR13## wherein p, p¹ , p², R² and R³ are as describedabove. Alternatively, a haloalcohol can be utilized in place of theamino epoxide.

The amino alcohol defined above is then reacted in a suitable solventwith the sulfonyl chloride R⁴ SO2Cl, the sulfonyl bromide R⁴ SO2Br orthe corresponding sulfonyl anhydride, preferably in the presence of anacid scavenger. Suitable solvents in which the reaction can be conductedinclude methylene chloride, tetrahydrofuran and the like. Suitable acidscavengers include triethylamine, pyridine and the like. The resultingsulfonamide derivative can be represented, depending on the epoxideutilized by the formulas ##STR14## wherein p, p¹, p², R², R³ and R⁴ areas defined above. These intermediates are useful for preparing inhibitorcompounds of the present invention.

The sulfonyl halides of the formula R⁴ SO₂ X can be prepared by thereaction of a suitable aryl, heteroaryl and benzo fused heterocycloGrignard or lithium reagents with sulfuryl chloride, or sulfur dioxidefollowed by oxidation with a halogen, preferably chlorine. Aryl,heteroaryl and benzo fused heterocyclo Grignard or lithium reagents canbe prepared from their corresponding halide (such as chloro or bromo)compounds which are commercially available or readily prepared fromcommercially available starting materials using known methods in theart. Also, thiols may be oxidized to sulfonyl chlorides using chlorinein the presence of water under carefully controlled conditions.Additionally, sulfonic acids, such as arylsulfonic acids, may beconverted to sulfonyl halides using reagents such as PCl, SOCl₂,ClC(O)C(O)Cl and the like, and also to anhydrides using suitabledehydrating reagents. The sulfonic acids may in turn be prepared usingprocedures well known in the art. Some sulfonic acids are commerciallyavailable. In place of the sulfonyl halides, sulfinyl halides (R⁴ SOX)or sulfenyl halides (R⁴ SX) can be utilized to prepare compounds whereinthe --SO₂ --moiety is replaced by an --SO--or --S--moiety, respectively.Arylsulfonic acids, benzo fused heterocyclo sulfonic acids or heteroarylsulfonic acids can be prepared by sulfonation of the aromatic ring bywell known methods in the art, such as by reaction with sulfuric acid,SO₃, SO₃ complexes, such as DMF(SO₃), pyridine(SO₃),N,N-dimethylacetamide(SO₃), and the like. Preferably, arylsulfonylhalides are prepared from aromatic compounds by reaction with DMF(SO₃)and SOCl₂ or ClC(O)C(O)Cl. The reactions may be performed stepwise or ina single pot.

Arylsulfonic acids, benzo fused heterocyclo sulfonic acids, heteroarylsulfonic acids, arylmercaptans, benzo fused heterocyclo mercaptans,heteroarylmercaptans, arylhalides, benzo fused heterocyclo halides,heteroarylhalides, and the like are commercially available or can bereadily prepared from starting materials commercially available usingstandard methods well known in the art. For example, a number ofsulfonic acids (R⁴ SO₃ H) represented by the formulas ##STR15## whereinA, B, Z, R⁶, R⁷ and R⁹ are as defined above, have been prepared from1,2-benzenedithiol, 2-mercaptophenol, 1,2-benzenediol,2-aminobenzothiazole, benzothiazole, 2-aminobenzimidazole,benzimidazole, and the like, which are commercially available, byCarter, U.S. Pat. No. 4,595,407; Ehrenfreund et al., U.S. Pat. No.4,634,465; Yoder et al., J. Heterocycl. Chem. 4:166-167 (1967); Cole etal., Aust. J. Chem. 33:675-680 (1980); Cabiddu et al., Synthesis 797-798(1976); Ncube et al., Tet. Letters 2345-2348 (1978); Ncube et al., Tet.Letters 255-256 (1977); Ansink & Cerfontain, Rec. Trav. Chim.Pays-Bas108:395-403 (1989); and Kajihara & Tsuchiya, EP 638564 A1, each of whichare incorporated herein by reference in their entirety. For example,1,2-benzenedithiol, 2-mercaptophenol or 1,2-benzenediol can be reactedwith R⁶ R⁷ C(L')₂, where L'is as defined below, preferably, Br or I, inthe presence of a base, such as hydroxide, or R⁶ R⁷ C═O in the presenceof acid, such as toluenesulfonic acid, or P₂ O₅, to prepare thesubstituted benzo fused heterocycle of formula ##STR16## which can thenbe sulfonylated to the sulfonic acid above. For example, CF₂ Br₂ or CD₂Br₂ can be reacted with 1,2-benzenedithiol, 2-mercaptophenol or1,2-benzenediol in the presence of base to produce the compounds##STR17## respectively, wherein A and B are 0 or S and D is a deuteriumatom. Also, when A and/or B represent S, the sulfur can be oxidizedusing the methods described below to the sulfone or sulfoxidederivatives.

Following preparation of the sulfonamide derivative, the aminoprotecting group P or p¹ and p² amino protecting groups are removedunder conditions which will not affect the remaining portion of themolecule. These methods are well known in the art and include acidhydrolysis, hydrogenolysis and the like. A preferred method involvesremoval of the protecting group, e.g., removal of a carbobenzoxy group,by hydrogenolysis utilizing palladium on carbon in a suitable solventsystem such as an alcohol, acetic acid, and the like or mixturesthereof. Where the protecting group is a t-butoxycarbonyl group, it canbe removed utilizing an inorganic or organic acid, e.g., HCl ortrifluoroacetic acid, in a suitable solvent system, e.g., dioxane ormethylene chloride. The resulting product is the amine salt derivative.

Following neutralization of the salt, the amine is then coupled to thesulfone/sulfoxidealkanoyl compound or an optical isomer thereof (such aswhere the group --CH(R¹)--is R or S), corresponding to the formula##STR18## wherein n, t and R5 are as defined above, and L is leavinggroup such as halide, anhydride, active ester, and the like.Alternatively, the sulfone/sulfoxide alkanoyl compound or an opticalisomer thereof can be coupled to the protected amine ##STR19## followedby deprotection and coupling to R⁴ SO₂ X, where X is Cl or Br and P',R², R³ and R⁴ is as defined above.

Such sulfone/sulfoxidealkanoyl compounds where n is 1 can be prepared byreacting a mercaptan of the formula R⁵ SH with a substitutedmethacrylate of the formula ##STR20## by way of a Michael Addition. Suchsubstituted methacrylates are commercially available or readily preparedfrom commercially available starting materials using standard methodswell known in the art. The Michael Addition is conducted in a suitablesolvent and in the presence of a suitable base, to produce thecorresponding thioether derivative represented by the formula ##STR21##wherein p³, R¹ and R⁵ are as defined above. Suitable solvents in whichthe Michael Addition can be conducted include alcohols such as, forexample, methanol, ethanol, butanol and the like, as well as ethers,e.g., THF, and acetonitrile, DMF, DMSO, and the like, including mixturesthereof. Suitable bases include Group I metal alkoxides such as, forexample sodium methoxide, sodium ethoxide, sodium butoxide and the likeas well as Group I metal hydrides, such as sodium hydride, includingmixtures thereof. The thioether derivative is converted into the##STR22## corresponding sulfone or sulfoxide of the formula by oxidizingthe thioether derivative with a suitable oxidation agent in a suitablesolvent. Suitable oxidation agents include, for example, hydrogenperoxide, sodium meta-perborate, oxone (potassium peroxy monosulfate),meta-chloroperoxybenzoic acid, periodic acid and the like, includingmixtures thereof. Suitable solvents include acetic acid (for sodiummeta-perborate) and, for other peracids, ethers such as THF and dioxane,and acetonitrile, DMF and the like, including mixtures thereof.

The sulfone/sulfoxide is then converted into the corresponding free acidof the formula ##STR23## utilizing a suitable base, e.g., lithiumhydroxide, sodium hydroxide, and the like, including mixtures thereof,in a suitable solvent, such as, for example, THF, acetonitrile, DMF,DMSO, methylene chloride and the like, including mixtures thereof. Thefree acid can then be converted into the sulfone/sulfoxidealkanoylcompound ##STR24## wherein n, t and R⁵ are as defined above, and L isleaving group such as halide, anhydride, active ester, and the like.Alternatively, the free acid can be resolved into its optical isomers(such as where the group --CH(R¹)--is R or S) using well known methodsin the art, such as by forming diastereomeric salts or esters andcrystallizing or chromatographing, and then converted into thesulfone/sulfoxidealkanoyl compound.

Alternatively, the thioether or corresponding protected thiol offormulas ##STR25## respectively, where n, L, R¹ and R⁵ are as definedabove, can be coupled to one of the amines ##STR26## followed byconversion to the protease inhibitors of the present invention. p⁴ is asulfur protecting group, such as acetyl, benzoyl and the like. Theacetyl and benzoyl groups can be removed by treatment with an inorganicbase or an amine, preferably ammonia, in an appropriate solvent such asmethanol, ethanol, isopropanol, toluene or tetrahydrofuran. Thepreferred solvent is methanol.

For example, one can couple the commercially available acid ##STR27## toone of the amines ##STR28## deacetylate the sulfur group, such as byhydrolysis with a suitable base, such as hydroxide, or an amine, such asammonia, and then react the resulting thiol with R⁵ L' agent, wherein R⁵and L' are as defined above, to afford compounds with one of thefollowing structures ##STR29## or specific diastereomeric isomersthereof. The sulfur can then be oxidized to the corresponding sulfone orsulfoxide using suitable oxidizing agents, as described above, to affordthe desired intermediate followed by further reactions to prepare thesulfonamide inhibitor, or directly to the sulfonamide inhibitor.Alternatively, the acid or the P³ protected acid can be deacetylated,reacted with R⁵ L' agent, deprotected and oxidized to the correspondingsulfone or sulfoxide using suitable oxidizing agents, as described aboveto afford the compound of formula ##STR30## wherein t and R⁵ are asdefined above. This sulfone/sulfoxide carboxylic acid can then becoupled to the amine intermediate described above followed by furtherreaction to prepare the sulfonamide inhibitor, or to the sulfonamideamine compound to produce the sulfonamide inhibitor directly. The L'group of the R⁵ L' agent is a leaving group such as a halide (chloride,bromide, iodide), mesylate, tosylate or triflate. The reaction of themercaptan with R⁵ L' is performed in the presence of a suitable base,such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo 5.4.0!undec-7-ene (DBu) and the like, in a suitable solvent such as toluene,tetrahydrofuran, methylene chloride or dimethylacetamide. The preferredbase is DBU and the preferred solvent is toluene or dimethylacetamide.Where R⁵ is a methyl group, R⁵ L' can be methyl chloride, methylbromide, methyl iodide, or dimethyl sulfate, and preferably methyliodide.

Alternatively, a substituted methacrylate of the formula ##STR31##wherein L' represents a leaving group as previously defined, p³ is asdefined above and R⁸ represents radicals which upon reduction of thedouble bond produce radicals of R¹, is reacted with R⁵ SM followed byoxidation, as described above, or a suitable sulfonating agent, such as,for example, a sulfinic acid represented by the formula R⁵ SO₂ M,wherein R⁵ is as defined above and M represents a metal adapted to forma salt of the acid, e.g., sodium, to produce the corresponding sulfonerepresented by the formula ##STR32## wherein p³, R⁵ and R⁸ are asdefined above. The sulfone is then deprotected to form the correspondingcarboxylic acid. For example, when P³ is a tertiary-butyl group, it canbe removed by treatment with an acid, such as hydrochloric acid ortrifluoracetic acid. The preferred method is using 4N hydrochloric acidin dioxane.

The resulting carboxylic acid is then asymmetrically hydrogenatedutilizing an asymmetric hydrogenation catalyst such as, for example, aruthenium-BINAP complex, to produce the reduced product, substantiallyenriched in the more desired isomer, represented by one of the formulas##STR33## wherein R¹ and R⁵ are as defined above. Where the more activeisomer has the R-stereochemistry, a Ru(R-BINAP) asymmetric hydrogenationcatalyst can be utilized. Conversely, where the more active isomer hasthe S-sterochemistry, a Ru(S-BINAP) catalyst can be utilized. where bothisomers are active, or where it is desired to have a mixture of the twodiastereomers, a hydrogenation catalyst such as platinum or palladium oncarbon can be utilized to reduce the above compound. The reducedcompound is then coupled to an amine as described above.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

All reagents were used as received without purification. All proton andcarbon NMR spectra were obtained on either a Varian VXR-300 or VXR-400nuclear magnetic resonance spectrometer.

The following Examples illustrate the preparation of inhibitor compoundsof the present invention and intermediates useful in preparing theinhibitor compounds of the present invention.

EXAMPLE 1 ##STR34## Preparation of 2S-Bis(phenylmethyl)aminol!benzenepropanol

Method 1:2S- Bis(phenylmethyl)amino!benzenepropanol from the DIBALReduction of N,N-bis(phenylmethyl)-L-Phenylalanine phenylmethyl ester

Step 1:

A solution of L-phenylalanine (50.0 g, 0.302 mol), sodium hydroxide(24.2 g, 0.605 mol) and potassium carbonate (83.6 g, 0.605 mol) in water(500 mL) was heated to 97° C. Benzyl bromide (108.5 mL, 0.605 mol) wasthen slowly added (addition time--25 min). The mixture was stirred at97° C. for 30 minutes under a nitrogen atmosphere. The solution wascooled to room temperature and extracted with toluene (2×250 mL). Thecombined organic layers were washed with water and brine, dried overmagnesium sulfate, filtered and concentrated to an oil. The identity ofthe product was confirmed as follows. Analytical TLC (10% ethylacetate/hexane, silica gel) showed major component at Rf value =0.32 tobe the desired tribenzylated compound,N,N-bis(phenylmethyl)-L-phenylalanine phenylmethyl ester. This compoundcan be purified by column chromatography (silica gel, 15% ethylacetate/hexane). Usually the product is pure enough to be used directlyin the next step without further purification. ¹ H NMR spectrum was inagreement with published literature. ¹ H NMR (CDCL³) ∂, 3.00 and 3.14(ABX-system, 2H, J_(AB) =14.1 Hz, J_(AX) =7.3 Hz and J_(BX) =5.9 Hz),3.54 and 3.92 (AB-System , 4 H, J_(AB) =3.9 Hz), 3.71 (t, 1H, J=7.6 Hz),5.11 and 5.23 (AB-System, 2H, J_(AB) =12.3 Hz), and 7.18 (m, 20 H).EIMS: m/z 434 (M-1).

Step 2:

The benzylated phenylalanine phenylmethyl ester (0.302 mol) from theprevious reaction was dissolved in toluene (750 mL) and cooled to -55°C. A 1.5M solution of DIBAL in toluene (443.9 mL, 0.666 mol) was addedat a rate to maintain the temperature between -55° to -50° C. (additiontime--1 hr). The mixture was stirred for 20 minutes under a nitrogenatmosphere and then quenched at --55° C. by the slow addition ofmethanol (37 ml). The cold solution was then poured into cold (5° C.)1.5N HC1 solution (1.8 L). The precipitated solid (approx. 138 g) wasfiltered off and washed with toluene. The solid material was suspendedin a mixture of toluene (400 mL) and water (100 ml). The mixture wascooled to 5° C. and treated with 2.5N NaOH (186 mL) and then stirred atroom temperature until solid dissolved. The toluene layer was separatedfrom the aqueous phase and washed with water and brine, dried overmagnesium sulfate, filtered and concentrated to a volume of 75 mL (89g). Ethyl acetate (25 mL) and hexane (25 mL) were added to the residueupon which the desired alcohol product began to crystallize. After 30min, an additional 50 mL hexane were added to promote furthercrystallization. The solid was filtered off and washed with 50 mL hexaneto give 34.9 g of first crop product. A second crop of product (5.6 g)was isolated by refiltering the mother liquor. The two crops werecombined and recrystallized from ethyl acetate (20 mL) and hexane (30mL) to give 40 g of βS-2- Bis(phenylmethyl)amino!benzenepropanol, 40%yield from L-phenylalanine. An additional 7 g (7%) of product can beobtained from recrystallization of the concentrated mother liquor. TLCof product Rf=0.23 (10% ethyl acetate/hexane, silica gel); ¹ H NMR(CDCl₃) ∂ 2.44 (m,1H,), 3.09 (m, 2H), 3.33 (m, 1H), 3.48 and 3.92(AB-System, 4H, J_(AB) =13.3 Hz), 3.52 (m, 1H) and 7.23 (m, 15H); α!_(D)25 +42.4 (c 1.45, CH₂ Cl₂); DSC 77.67° C.; Anal. Calcd. for C₂₃ H₂₅ ON:C, 83.34; H, 7.60; N, 4.23. Found: C, 83.43; H, 7.59; N, 4.22. HPLC onchiral stationary phase: Cyclobond I SP column (250×4.6 mm I.D.), mobilephase: methanol/triethyl ammonium acetate buffer pH 4.2 (58:42, v/v),flow-rate of 0.5 ml/min, detection with detector at 230 nm and atemperature of 0° C. Retention time: 11.25 min., retention time of thedesired product enantiomer: 12.5 min.

Method 2: Preparation of βS-2- Bis(phenylmethyl)amino! benzene-propanolfrom the N,N-Dibenzylation of L-Phenylalaninol

L-phenylalaninol (176.6 g, 1.168 mol) was added to a stirred solution ofpotassium carbonate (484.6 g, 3.506 mol) in 710 mL of water. The mixturewas heated to 65° C. under a nitrogen atmosphere. A solution of benzylbromide (400 g, 2.339 mol) in 3A ethanol (305 mL) was added at a ratethat maintained the temperature between 60°-68° C. The biphasic solutionwas stirred at 65° C. for 55 min and then allowed to cool to 10° C. withvigorous stirring. The oily product solidified into small granules. Theproduct was diluted with 2.0 L of tap water and stirred for 5 minutes todissolve the inorganic by products. The product was isolated byfiltration under reduced pressure and washed with water until the pH is7. The crude product obtained was air dried overnight to give a semi-drysolid (407 g) which was recrystallized from 1.1 L of ethylacetate/heptane (1:10 by volume). The product was isolated by filtration(at -8° C.), washed with 1.6 L of cold (-10° C. ) ethyl acetate/heptane(1:10 by volume) and air-dried to give 339 g (88% yield) of :βS-2-Bis(phenylmethyl)amino!benzene-propanol, Mp=71.5°-73.0° C. More productcan be obtained from the mother liquor if necessary. The otheranalytical characterization was identical to compound prepared asdescribed in Method 1.

EXAMPLE 2 ##STR35## Preparation of 2S-Bis(phenylmethyl)amino!benzenepropanaldehyde

Method 1:

2S- Bis(phenylmethyl)amino!benzene-propanol (200 g, 0.604 mol) wasdissolved in triethylamine (300 mL, 2.15 mol). The mixture was cooled to-12° C. and a solution of sulfur trioxide/pyridine complex (380 g, 2.39mol) in DMSO (1.6 L) was added at a rate to maintain the temperaturebetween 8°-17° C. (addition time--1.0 h). The solution was stirred atambient temperature under a nitrogen atmosphere for 1.5 hour at whichtime the reaction was complete by TLC analysis (33% ethylacetate/hexane, silica gel). The reaction mixture was cooled with icewater and quenched with 1.6 L of cold water (10°-15° C.) over 45minutes. The resultant solution was extracted with ethyl acetate (2.0L), washed with 5% citric acid (2.0 L), and brine (2.2 L), dried overMgSO₄ (280 g) and filtered. The solvent was removed on a rotaryevaporator at 35°-40° C., and then dried under vacuum to give 198.8 g of2S- Bis-(phenylmethyl)amino!benzene propanaldehyde as a pale yellow oil(99.9%). The crude product obtained was pure enough to be used directlyin the next step without purification. The analytical data of thecompound were consistent with the published literature. α!_(D) 25=-92.9°(c 1.87, CH₂ Cl₂); ¹ H NMR (400 MHz, CDCl₃) ∂, 2.94 and 3.15(ABX-System, 2H, J_(AB) =13.9 Hz, J_(AX) =7.3 Hz and J_(BX) =6.2 Hz),3.56 (t, 1H, 7.1 Hz), 3.69 and 3.82 (AB-System, 4H, J_(AB) =13.7 Hz),7.25 (m, 15 H) and 9.72 (s, 1H); HRMS Calcd for (M+1) C₂₃ H₂₄ NO330.450, found: 330.1836. Anal. Calcd. for C₂₃ H₂₃ ON: C, 83.86; H,7.04; N, 4.25. Found: C, 83.64; H, 7.42; N, 4.19. HPLC on chiralstationary phase:(S,S) Pirkle-Whelk-O 1 column (250×4.6 mm I.D.), mobilephase: hexane/isopropanol (99.5:0.5, v/v), flow-rate: 1.5 ml/min,detection with UV detector at 210 nm. Retention time of the desiredS-isomer: 8.75 min., retention time of the R-enantiomer 10.62 min.

Method 2:

A solution of oxalyl chloride (8.4 ml, 0.096 mol) in dichloromethane(240 ml) was cooled to -740° C. A solution of DMSO (12.0 ml, 0.155 mol)in dichloromethane (50 ml) was then slowly added at a rate to maintainthe temperature at -74° C. (addition time ˜1.25 hr). The mixture wasstirred for 5 min. followed by addition of a solution of βS-2-bis(phenylmethyl)amino!benzene-propanol (0.074 mol) in 100 ml ofdichloromethane (addition time -20 min., temp. -75° C. to -68° C.). Thesolution was stirred at -78° C. for 35 minutes under a nitrogenatmosphere. Triethylamine (41.2 ml, 0.295 mol) was then added over 10min. (temp. -78° to -68° C.) upon which the ammonium salt precipitated.The cold mixture was stirred for 30 min. and then water (225 ml) wasadded. The dichloromethane layer was separated from the aqueous phaseand washed with water, brine, dried over magnesium sulfate, filtered andconcentrated. The residue was diluted with ethyl acetate and hexane andthen filtered to further remove the ammonium salt. The filtrate wasconcentrated to give αS- bis(phenylmethyl)amino! benzenepropanaldehyde.The aldehyde was carried on to the next step without purification.

Method 3:

To a mixture of 1.0 g(3.0 mmoles) of βS-2-bis(phenylmethyl)amino!benzenepropanol 0.531 g(4.53 mmoles) of N-methylmorpholine, 2.27 g of molecular sieves(4A) and 9.1 mL of acetonitrilewas added 53 mg (0.15 mmoles) of tetrapropylammonium perruthenate(TPAP).The mixture was stirred for 40 minutes at room temperature andconcentrated under reduced pressure. The residue was suspended in 15 mLof ethyl acetate, filtered through a pad of silica gel. The filtrate wasconcentrated under reduced pressure to give a product containingapproximately 50% of αS-2- bis(phenylmethyl) amino!benzenepropanaldehyde as a pale yellow oil.

Method 4:

To a solution of 1.0 g (3.02 mmoles) of βS-2-bis(phenylmethyl)amino!benzenepropanol in 9.0 mL of toluene was added4.69 mg(0.03 mmoles) of 2,2,6,6-tetramethyl-1-piperidinyloxy, freeradical (TEMPO), 0.32 g(3.11 mmoles) of sodium bromide, 9.0 mL of ethylacetate and 1.5 mL of water. The mixture was cooled to 0° C. and anaqueous solution of 2.87 mL of 5% household bleach containing 0.735g(8.75 mmoles) of sodium bicarbonate and 8.53 mL of water was addedslowly over 25 minutes. The mixture was stirred at 0° C. for 60 minutes.Two more additions (1.44 mL each) of bleach was added followed bystirring for 10 minutes. The two phase mixture was allowed to separate.The aqueous layer was extracted twice with 20 mL of ethyl acetate. Thecombined organic layer was washed with 4.0 mL of a solution containing25 mg of potassium iodide and water (4.0 mL), 20 mL of 10% aqueoussodium thiosulfate solution and then brine solution. The organicsolution was dried over magnesium sulfate, filtered and concentratedunder reduced pressure to give 1.34 g of crude oil containing a smallamount of the desired product aldehyde, αS- bis(phenylmethyl)amino!benzenepropanaldehyde.

Method 5:

Following the same procedures as described in Method 1 of this Exampleexcept 3.0 equivalents of sulfur trioxide pyridine complex was used andαS- bis(phenylmethyl)amino!benzenepropanaldehyde was isolated incomparable yields.

Example 3 ##STR36## Preparation ofN,N-dibenzyl-3(S)-amino-1,2-(S)-epoxy-4-phenylbutane

Method 1:

A solution of αS- Bis(phenylmethyl)amino!benzene-propanaldehyde (191.7g, 0.58 mol) and chloroiodomethane (56.4 mL, 0.77 mol) intetrahydrofuran (1.8 L) was cooled to -30° to -35° C. (coldertemperature such as -70° C. also worked well but warmer temperatures aremore readily achieved in large scale operations) in a stainless steelreactor under a nitrogen atmosphere. A solution of n-butyl lithium inhexane (1.6M, 365 mL, 0.58 mol) was then added at a rate that maintainedthe temperature below -25° C. After addition the mixture was stirred at-30° to -35° C. for 10 minutes. More additions of reagents were carriedout in the following manner: (1) additional chloroiodomethane (17 mL)was added, followed by n-butyl lithium (110 mL) at <-25° C. Afteraddition the mixture was stirred at -30° to -35° C. for 10 minutes. Thiswas repeated once. (2) Additional chloroiodomethane (8.5 mL, 0.11 mol)was added, followed by n-butyl lithium (55 mL, 0.088 mol) at <-25° C.After addition the mixture was stirred at -30° to -35° C. for 10minutes. This was repeated 5 times. (3) Additional chloroiodomethane(8.5 mL, 0.11 mol) was added, followed by n-butyl lithium (37 mL, 0.059mol) at <-25° C. After addition the mixture was stirred at -30° to -35°C. for 10 minutes. This was repeated once. The external cooling wasstopped and the mixture warmed to ambient temp. over 4 to 16 hours whenTLC (silica gel, 20% ethyl acetate/hexane) indicated that the reactionwas completed. The reaction mixture was cooled to 10° C. and quenchedwith 1452 g of 16% ammonium chloride solution (prepared by dissolving232 g of ammonium chloride in 1220 mL of water), keeping the temperaturebelow 23° C. The mixture was stirred for 10 minutes and the organic andaqueous layers were separated. The aqueous phase was extracted withethyl acetate (2×500 mL). The ethyl acetate layer was combined with thetetrahydrofuran layer. The combined solution was dried over magnesiumsulfate (220 g), filtered and concentrated on a rotary evaporator at 65°C. The brown oil residue was dried at 70° C. in vacuo (0.8 bar) for 1 hto give 222.8 g of crude material. (The crude product weight was >100%.Due to the relative instability of the product on silica gel, the crudeproduct is usually used directly in the next step without purification).The diastereomeric ratio of the crude mixture was determined by protonNMR: (2S)/(2R): 86:14. The minor and major epoxide diastereomers werecharacterized in this mixture by tlc analysis (silica gel, 10% ethylacetate/hexane), Rf=0.29 & 0.32, respectively. An analytical sample ofeach of the diastereomers was obtained by purification on silica-gelchromatography (3% ethyl acetate/hexane) and characterized as follows:

N,N,αS-Tris(phenylmethyl)-2S-oxiranemethanamine

¹ H NMR (400 MHz, CDCl₃) ∂ 2.49 and 2.51 (AB-System, 1H, J_(AB) =2.82),2.76 and 2.77 (AB-System, 1H, J_(AB) =4.03), 2.83 (m, 2H), 2.99 & 3.03(AB-System, 1H, J_(AB) =10.1 Hz), 3.15 (m, 1H), 3.73 & 3.84 (AB-System,4H, J_(AB) =14.00), 7.21 (m, 15H); ¹³ C NMR (400 MHz,CDCl₃) ∂ 139.55,129.45, 128.42, 128.14, 128.09, 126.84, 125.97, 60.32, 54.23, 52.13,45.99, 33.76; HRMS Calcd for C₂₄ H₂₆ NO (M+1) 344.477, found 344.2003.

N,N,αS-Tris(phenylmethyl)-2R-oxiranemethanamine ¹ H NMR (300 MHz, CDCl₃)δ 2.20 (m, 1H), 2.59 (m, 1H), 2.75 (m, 2H), 2.97 (m, 1H), 3.14 (m, 1H),3.85 (AB-System, 4H), 7.25 (m, 15H). HPLC on chiral stationary phase:Pirkle-Whelk-O 1 column (250×4.6 mm I.D.), mobile phase:hexane/isopropanol (99.5:0.5, v/v), flow-rate: 1.5 ml/min, detectionwith UV detector at 210 nm. Retention time of(8): 9.38 min., retentiontime of enantiomer of (4): 13.75 min.

Method 2:

A solution of the crude aldehyde 0.074 mol and chloroiodomethane (7.0ml, 0.096 mol) in tetrahydrofuran (285 ml) was cooled to -78° C., undera nitrogen atmosphere. A 1.6M solution of n-butyl lithium in hexane (25ml, 0.040 mol) was then added at a rate to maintain the temperature at-75° C. (addition time--15 min.). After the first addition, additionalchloroiodo-methane (1.6 ml, 0.022 mol) was added again, followed byn-butyl lithium (23 ml, 0.037 mol), keeping the temperature at -75° C.The mixture was stirred for 15 min. Each of the reagents,chloroiodomethane (0.70 ml, 0.010 mol) and n-butyl lithium (5 ml, 0.008mol) were added 4 more times over 45 min. at -75° C. The cooling bathwas then removed and the solution warmed to 22° C. over 1.5 hr. Themixture was poured into 300 ml of saturated aq. ammonium chloridesolution. The tetrahydrofuran layer was separated. The aqueous phase wasextracted with ethyl acetate (1×300 ml). The combined organic layerswere washed with brine, dried over magnesium sulfate, filtered andconcentrated to give a brown oil (27.4 g). The product could be used inthe next step without purification. The desired diastereomer can bepurified by recrystallization at a subsequent step. The product couldalso be purified by chromatography.

Method 3:

A solution of αS- Bis(phenylmethyl)amino!benzene-propanaldehyde (178.84g, 0.54 mol) and bromochloro-methane (46 mL, 0.71 mol) intetrahydrofuran (1.8 L) was cooled to -30° to -35° C. (coldertemperature such as -70° C. also worked well but warmer temperatures aremore readily achieved in large scale operations) in a stainless steelreactor under a nitrogen atmosphere. A solution of n-butyl lithium inhexane (1.6M, 340 mL, 0.54 mol) was then added at a rate that maintainedthe temperature below -250° C. After addition the mixture was stirred at-30° to -35° C. for 10 minutes. More additions of reagents were carriedout in the following manner: (1) additional bromochloromethane (14 mL)was added, followed by n-butyl lithium (102 mL) at <-25° C. Afteraddition the mixture was stirred at -30° to -35° C. for 10 minutes. Thiswas repeated once. (2) Additional bromochloromethane (7 mL, 0.11 mol)was added, followed by n-butyl lithium (51 mL, 0.082 mol) at <-25° C.After addition the mixture was stirred at -30° to -35° C. for 10minutes. This was repeated 5 times. (3) Additional bromochloromethane (7mL, 0.11 mol) was added, followed by n-butyl lithium (51 mL, 0.082 mol)at <-25° C. After addition the mixture was stirred at -30° to -35° C.for 10 minutes. This was repeated once. The external cooling was stoppedand the mixture warmed to ambient temp. over 4 to 16 hours when TLC(silica gel, 20% ethyl acetate/hexane) indicated that the reaction wascompleted. The reaction mixture was cooled to 10° C. and quenched with1452 g of 16% ammonium chloride solution (prepared by dissolving 232 gof ammonium chloride in 1220 mL of water), keeping the temperature below23° C. The mixture was stirred for 10 minutes and the organic andaqueous layers were separated. The aqueous phase was extracted withethyl acetate (2×500 mL). The ethyl acetate layer was combined with thetetrahydrofuran layer. The combined solution was dried over magnesiumsulfate (220 g), filtered and concentrated on a rotary evaporator at 65°C. The brown oil residue was dried at 70° C. in vacuo (0.8 bar) for 1 hto give 222.8 g of crude material.

Method 4:

Following the same procedures as described in Method 3 of this Exampleexcept the reaction temperatures were at -20° C. The resultingN,N,αS-tris(phenylmethyl)-2S-oxiranemethanamine was a diastereomericmixture of lesser purity then that of Method 3.

Method 5:

Following the same procedures as described in Method 3 of this Exampleexcept the reaction temperatures were at -70--78° C. The resultingN,N,αS-tris(phenylmethyl)-2S-oxiranemethanamine was a diastereomericmixture, which was used directly in the subsequent steps withoutpurification.

Method 6:

Following the same procedures as described in Method 3 of this Exampleexcept a continuous addition of bromochloromethane and n-butyl lithiumwas used at -30° to -35° C. After the reaction and work up procedures asdescribed in Method 3 of this Example, the desiredN,N,αS-tris(phenylmethyl)-2S-oxiranemethanamine was isolated incomparable yields and purities.

Method 7:

Following the same procedures as described in Method 2 of this Exampleexcept dibromomethane was used instead of chloroiodomethane. After thereaction and work up procedures as described in Method 2 of thisExample, the desired N,N,αS-tris(phenylmethyl)-2S-oxirane-methanaminewas isolated.

EXAMPLE 4 ##STR37## Preparation of N- 3(S)-N,N-bis(phenylmethyl)aminol!-2(R)-hydroxy-4-phenylbutyl!-N-isobutylamine

To a solution of crudeN,N-dibenzyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane (388.5 g, 1.13 mol)in isopropanol (2.7 L) (or ethyl acetate) was added isobutylamine (1.7kgm, 23.1 mol) over 2 min. The temperature increased from 25° C. and to30° C. The solution was heated to 82° C. and stirred at this temperaturefor 1.5 hours. The warm solution was concentrated under reduced pressureat 65° C., the brown oil residue was transferred to a 3-L flask anddried in vacuo (0.8 mm Hg) for 16 h to give 450 g of 3S-N,N-bis(phenylmethyl)amino-4-phenylbutan-2R-ol as a crude oil.

An analytical sample of the desired major diastereomeric product wasobtained by purifying a small sample of crude product by silica gelchromatography (40% ethyl acetate/hexane). Tlc analysis: silica gel, 40%ethyl acetate/hexane; Rf=0.28; HPLC analysis: ultrasphere ODS column,25% triethylamino-/phosphate buffer pH 3-acetonitrile, flow rate 1mL/min, UV detector; retention time 7.49 min.; HRMS Calcd for C₂₈ H₂₇ N₂O (M+1) 417.616, found 417.2887.An analytical sample of the minordiastereomeric product, 3S-N,N-bis(phenylmethyl)amino!1-(2-methylpropyl)amino-4-phenylbutan-2S-olwas also obtained by purifying a small sample of crude product by silicagel chromatography (40% ethyl acetate/hexane).

EXAMPLE 5 ##STR38## Preparation of N- 3(S)-N,N-bis(phenylmethyl)aminol!-2(R)-hydroxy-4-phenylbutyl!-N-isobutylamine•oxalicacid salt

To a solution of oxalic acid (8.08 g, 89.72 mmol) in methanol (76 mL)was added a solution of crude 3(S)- N,N-bis(phenylmethyl)amino!-1-(2-methylpropyl)amino-4-phenyl butan-2(R)-ol {39.68 g, whichcontains about 25.44 g (61.06 mmol) of 3(S),2(R) isomer and about 4.49 g(10.78 mmol) of 3(S),2(S) isomer} in ethyl acetate (90 mL) over 15minutes. The mixture was stirred at room temperature for about 2 hours.Solid was isolated by filtration, washed with ethyl acetate (2×20 mL)and dried in vacuo for about 1 hour to yield 21.86 g (70.7% isomerrecovery) of 97% diastereomerically pure salt (based on HPLC peakareas). HPLC analysis: Vydec-peptide/protein C18 column, UV detector 254nm, flow rate 2 mL/min., gradient {A=0.05% trifluoroacetic acid inwater, B=0.05% trifluoroacetic acid in acetonitrile, 0 min. 75% A/25% B,30 min. 10% A/90% B, 35 min. 10% A/90% B, 37 min. 75% A/25% B};Retention time 10.68 min. (3(S),2(R) isomer) and 9.73 min. (3(S),2(S)isomer). M_(p) =174.99° C.; Microanalysis: Calc.: C 71.05%, H 7.50%, N5.53%; Found: C 71.71%, H 7.75%, N 5.39%.

Alternatively, oxalic acid dihydrate (119 g, 0.94 mole) was added to a5000 mL round bottom flask fitted with a mechanical stirrer and adropping funnel. Methanol (1000 ml) was added and the mixture stirreduntil dissolution was complete. A solution of crude 3(S)-N,N-bis(phenylmethyl)amino!-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol in ethyl acetate (1800 ml, 0.212 g aminoalcohol isomers/mL, 0.9160 moles) was added over a twenty minute period.The mixture was stirred for 18 hours and the solid product was isolatedby centrifugation in six portions at 400G. Each portion was washed with125 mL of ethyl acetate. The salt was then collected and dried overnightat 1 torr to yield 336.3 g of product (71% based upon total aminoalcohol). HPLC/MS (electrospray) was consistent with the desired product(m/z 417 M+H!⁺).

Alternatively, crude 3(S)- N,N-bis(phenylmethyl)amino!-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol (5 g) was dissolvedin methyl-tert-butylether (MTBE) (10 mL) and oxalic acid (1 g) inmethanol (4 mL) was added. The mixture was stirred for about 2 hours.The resulting solid was filtered, washed with cold MTBE and dried toyield 2.1 g of white solid of about 98.9% diastereomerically pure (basedon HPLC peak areas).

EXAMPLE 6 Preparation of N- 3(S)-N,N-bis(phenylmethyl)amino!-2(R)-hydroxy-4-phenylbutyl!-N-isobutylamine•aceticacid salt

To a solution of crude 3(S)- N,N-bis(phenylmethyl)amino!-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol inmethyl-tert-butylether (MTBE) (45 mL, 1.1 g amino alcohol isomers/mL)was added acetic acid (6.9 mL) dropwise. The mixture was stirred forabout 1 hour at room temperature. The solvent was removed in vacuo toyield a brown oil about 85% diastereomerically pure product (based onHPLC peak areas). The brown oil was crystallized as follows: 0.2 g ofthe oil was dissolved in the first solvent with heat to obtain a clearsolution, the second solvent was added until the solution became cloudy,the mixture was heated again to clarity, seeded with about 99%diastereomerically pure product, cooled to room temperature and thenstored in a refrigerator overnight. The crystals were filtered, washedwith the second solvent and dried. The diastereomeric purity of thecrystals was calculated from the HPLC peak areas. The results are shownin Table 1.

                  TABLE 1                                                         ______________________________________                                                                           Diastereo-                                 First     Second  Solvent   Recovery                                                                             meric                                      Solvent   Solvent Ratio     Weight (g)                                                                           Purity (%)                                 ______________________________________                                        MTBE      Heptane 1:10      0.13   98.3                                       MTBE      Hexane  1:10      0.03   99.6                                       Methanol  Water   1:1.5     0.05   99.5                                       Toluene   Heptane 1:10      0.14   98.7                                       Toluene   Hexane  1:10      0.10   99.7                                       ______________________________________                                    

Alternatively, crude 3(S)- N,N-bis(phenylmethyl)amino!-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol (50.0 g, whichcontains about 30.06 g (76.95 mmol) of 3(S),2(R) isomer and about 5.66 g(13.58 mmol) of 3(S),2(S) isomer) was dissolved inmethyl-tert-butylether (45.0 mL). To this solution was added acetic acid(6.90 mL, 120.6 mmol) over a period of about 10 min. The mixture wasstirred at room temperature for about 1 hour and concentrated underreduced pressure. The oily residue was purified by recrystallizationfrom methyl-tert-butylether (32 mL) and heptane (320 mL). Solid wasisolated by filtration, washed with cold heptane and dried in vacuo forabout 1 hour to afford 21.34 g (58.2% isomer recovery) of 96%diastereomerically pure monoacetic acid salt (based on HPLC peak areas).M_(p) =105°-106° C.; Microanalysis: Calc.: C 75.53%, H 8.39%, N 5.87%;Found: C 75.05%, H 8.75%, N 5.71%.

EXAMPLE 7 Preparation of N- 3(S)-N,N-bis(phenylmethyl)amino!-2(R)-hydroxy-4-phenylbutyl!-N-isobutylamine•L-tartaricacid salt

Crude 3(S)-N,N-bis(phenylmethyl)amino!-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol(10.48 g, which contains about 6.72 g (16.13 mmol) of 3(S),2(R) isomerand about 1.19 g (2.85 mmol) of 3(S),2(S) isomer) was dissolved intetrahydrofuran (10.0 mL). To this solution was added a solution ofL-tartaric acid (2.85 g, 19 mmol) in methanol (5.0 mL) over a period ofabout 5 min. The mixture was stirred at room temperature for about 10min. and concentrated under reduced pressure. Methyl-tert-butylether(20.0 mL) was added to the oily residue and the mixture was stirred atroom temperature for about 1 hour. Solid was isolated by filtration toafford 7.50 g of crude salt. The crude salt was purified byrecrystallization from ethyl acetate and heptane at room temperature toyield 4.13 g (45.2% isomer recovery) of 95% diastereomerically pureL-tartaric acid salt (based on HPLC peak areas). Microanalysis: Calc.: C67.76%, H 7.41%, N 4.94%; Found: C 70.06%, H 7.47%, N 5.07%.

EXAMPLE 8 Preparation of N- 3(S)-N,N-bis(phenylmethyl)amino!-2(R)-hydroxy-4-phenylbutyl!-N-isobutylamine•edihydrochloricacid salt

Crude 3(S)- N,N-bis(phenylmethyl)amino!-1-(2-methylpropyl)amino-4-phenylbutan-2 (R) -ol (10.0 g, whichcontains about 6.41 g (15.39 mmol) of 3(S),2(R) isomer and about 1.13 g(2.72 mmol) of 3(S),2(S) isomer} was dissolved in tetrahydrofuran (20.0mL). To this solution was added hydrochloric acid (20 mL, 6.0N) over aperiod of about 5 min. The mixture was stirred at room temperature forabout 1 hour and concentrated under reduced pressure. The residue wasrecrystallized from ethanol at 0° C. to yield 3.20 g (42.7% isomerrecovery) of 98% diastereomerically pure dihydrochloric acid salt (basedon HPLC peak areas). Microanalysis: Calc.: C 68.64%, H 7.76%, N 5.72%;Found: C 68.79%, H 8.07%, N 5.55%.

EXAMPLE 9 Preparation of N- 3(S)-N,N-bis(phenylmethyl)amino!-2(R)-hydroxy-4-phenylbutyl!-N-isobutylamine•etoluenesulfonicacid salt

Crude 3(S)- N,N-bis(phenylmethyl)amino!-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol (5.0 g, whichcontains about 3.18 g (7.63 mmol) of 3(S),2(R) isomer and about 0.56 g(1.35 mmol) of 3(S),2(S) isomer} was dissolved in methyl-tert-butylether(10.0 mL). To this solution was added a solution of toluenesulfonic acid(2.28 g, 12 mmol) in methyl-tert-butylether (2.0 mL) and methanol (2.0mL) over a period of about 5 min. The mixture was stirred at roomtemperature for about 2 hours and concentrated under reduced pressure.The residue was recrystallized from methyl-tert-butylether and heptaneat 0° C., filtered, washed with cold heptane and dried in vacuo to yield1.85 g (40.0% isomer recovery) of 97% diastereomerically puremonotoluenesulfonic acid salt (based on HPLC peak areas).

EXAMPLE 10 Preparation of N- 3(S)-N,N-bis(phenylmethyl)amino!-2(R)-hydroxy-4-phenylbutyl!-N-isobutylamine•methanesulfonicacid salt

Crude 3(S)- N,N-bis(phenylmethyl)amino!-1-(2-methylpropyl)amino-4-phenylbutan-2(R)-ol (10.68 g, whichcontains about 6.85 g (16.44 mmol) of 3(S),2(R) isomer and about 1.21 g(2.90 mmol) of 3(S),2(S) isomer} was dissolved in tetrahydrofuran (10.0mL). To this solution was added methanesulfonic acid (1.25 mL, 19.26mmol). The mixture was stirred at room temperature for about 2 hours andconcentrated under reduced pressure. The oily residue was recrystallizedfrom methanol and water at 0° C., filtered, washed with coldmethanol/water (1:4) and dried in vacuo to yield 2.40 g (28.5% isomerrecovery) of 98% diastereomerically pure monomethanesulfonic acid salt(based on HPLC peak areas).

EXAMPLE 11 Preparation of N-benzyl-L-phenylalaninol

Method 1:

L-Phenylalaninol (89.51 g, 0.592 moles) was dissolved in 375 mL ofmethanol under inert atmosphere, 35.52 g (0.592 moles) of glacial aceticacid and 50 mL of methanol was added followed by a solution of 62.83 g(0.592 moles) of benzaldehyde in 100 mL of methanol. The mixture wascooled to approximately 15° C. and a solution of 134.6 g(2.14 moles) ofsodium cyanoborohydride in 700 mL of methanol was added in approximately40 minutes, keeping the temperature between 15° C. and 25° C. Themixture was stirred at room temperature for 18 hours. The mixture wasconcentrated under reduced pressure and partitioned between 1 L of 2Mammonium hydroxide solution and 2 L of ether. The ether layer was washedwith 1 L of 1M ammonium hydroxide solution, twice with 500 mL water, 500mL of brine and dried over magnesium sulfate for 1 hour. The ether layerwas filtered, concentrated under reduced pressure and the crude solidproduct was recrystallized from 110 mL of ethyl acetate and 1.3 L ofhexane to give 115 g (81% yield) of N-benzyl-L-phenylalaninol as a whitesolid.

Method 2:

L-Phenylalaninol (5 g, 33 mmoles) and 3.59 g (33.83 mmoles) ofbenzaldehyde were dissolved in 55 mL of 3A ethanol under inertatmosphere in a Parr shaker and the mixture was warmed to 60° C. for 2.7hours. The mixture was cooled to approximately 25° C. and 0.99 g of 5%platinum on carbon was added and the mixture was hydrogenated at 60 psiof hydrogen and 40° C. for 10 hours. The catalyst was filtered off, theproduct was concentrated under reduced pressure and the crude solidproduct was recrystallized from 150 mL of heptane to give 3.83 g (48%yield) of N-benzyl-L-phenylalaninol as a white solid.

EXAMPLE 12 Preparation of N-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninol

N-benzyl-L-phenylalaninol (2.9 g, 12 mmoles) was dissolved in 3 mL oftriethylamine and 27 mL of methanol and 5.25 g (24.1 mmoles) ofdi-tert-butyl dicarbonate was added. The mixture was warmed to 60° C.for 35 minutes and concentrated under reduced pressure. The residue wasdissolved in 150 mL of ethyl acetate and washed twice with 10 mL of cold(0°-5° C., dilute hydrochloric acid (pH 2.5 to 3), 15 mL of water, 10 mLof brine, dried over magnesium sulfate, filtered and concentrated underreduced pressure. The crude product oil was purified by silica gelchromatography (ethyl acetate: hexane, 12:3 as eluting solvent) to give3.98 g (97% yield) of colorless oil.

EXAMPLE 13 Preparation of N-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninal

Method 1:

To a solution of 0.32 g(0.94 mmoles) ofN-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninol in 2.8 mL of toluene wasadded 2.4 mg (0.015 mmoles) of 2,2,6,6-tetramethyl-l-piperidinyloxy,free radical (TEMPO), 0.1 g (0.97 mmoles) of sodium bromide, 2.8 mL ofethyl acetate and 0.34 mL of water. The mixture was cooled to 0° C. andan aqueous solution of 4.2 mL of 5% household bleach containing 0.23 g(3.0 mL, 2.738 mmoles) of sodium bicarbonate was added slowly over 30minutes. The mixture was stirred at 0° C. for 10 minutes. Three moreadditions (0.4 mL each) of bleach was added followed by stirring for 10minutes after each addition to consume all the stating material. The twophase mixture was allowed to separate. The aqueous layer was extractedtwice with 8 mL of toluene. The combined organic layer was washed with1.25 mL of a solution containing 0.075 g of potassium iodide, sodiumbisulfate(0.125 g) and water(1.1 mL), 1.25 mL of 10% aqueous sodiumthiosulfate solution, 1.25 mL of pH 7 phosphate buffer and 1.5 mL ofbrine solution. The organic solution was dried over magnesium sulfate,filtered and concentrated under reduced pressure to give 0.32 g (100%yield) of N-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninal.

Method 2:

To a solution of 2.38 g (6.98 mmoles) ofN-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninol in 3.8 mL (27.2 mmoles)of triethylamine at 10° C. was added a solution of 4.33 g (27.2 mmoles)of sulfur trioxide pyridine complex in 17 mL of dimethyl sulfoxide. Themixture was warmed to room temperature and stirred for one hour. Water(16 mL) was added and the mixture was extracted with 20 mL of ethylacetate. The organic layer was washed with 20 mL of 5% citric acid, 20mL of water, 20 mL of brine, dried over magnesium sulfate and filtered.The filtrate was concentrated under reduced pressure to give 2.37 g(100% yield) of N-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninal.

EXAMPLE 14 ##STR39## Preparation of 3(S)-N-(t-butoxycarbonyl)-N-benzylamino!-1, 2-(S)-epoxy-4-phenylbutane

Method 1:

A solution of 2.5 g (7.37 mmoles) ofN-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninal and 0.72 mL ofchloroiodomethane in 35 mL of THF was cooled to -78° C. A 4.64 mL of asolution of n-butyllithium (1.6M in hexane, 7.42 mmoles) was addedslowly, keeping the temperature below -70° C. The mixture was stirredfor 10 minutes between -70° to -75° C. Two additional portions of 0.22mL of chloroiodomethane and 1.4 mL of n-butyllithium was addedsequentially and the mixture was stirred for 10 minutes between -70° to-75° C. after each addition. Four additional portions of 0.11 mL ofchloroiodomethane and 0.7 mL of n-butyllithium was added sequentiallyand the mixture was stirred for 10 minutes between -70° to -75° C. aftereach addition. The mixture was warmed to room temperature for 3.5 hours.The product was quenched at below 5° C. with 24 mL of ice-cold water.The biphasic layers were separated and the aqueous layer was extractedtwice with 30 mL of ethyl acetate. The combined organic layers waswashed three times with 10 mL water, then with 10 mL brine, dried oversodium sulfate, filtered and concentrated under reduced pressure to give2.8 g of a yellow crude oil. This crude oil (>100% yield) is a mixtureof the diastereomeric epoxidesN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine andN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanamine. Thecrude mixture is used directly in the next step without purification.

Method 2:

To a suspension of 2.92 g (13.28 mmoles) of trimethylsulfoxonium iodidein 45 mL of acetonitrile was added 1.49 g (13.28 mmoles) of potassiumt-butoxide. A solution of 3.0 g (8.85 mmoles) ofN-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninal in 18 mL of acetonitrilewas added and the mixture was stirred at room temperature for one hour.The mixture was diluted with 150 mL of water and extracted twice with200 mL of ethyl acetate. The organic layers were combined and washedwith 100 mL water, 50 mL brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give 3.0 g of a yellow crude oil.The crude product was purified by silica gel chromatography (ethylacetate/hexane: 1:8 as eluting solvent) to give 1.02 g (32.7% yield) ofa mixture of the two diastereomersN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine andN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanamine.

Method 3:

To a suspension of 0.90 g (4.42 mmoles) of trimethylsulfonium iodide in18 mL of acetonitrile was added 0.495 g (4.42 mmoles) of potassiumt-butoxide. A solution of 1.0 g (2.95 mmoles) ofN-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninal in 7 mL of acetonitrilewas added and the mixture was stirred at room temperature for one hour.The mixture was diluted with 80 mL of water and extracted twice with 80mL of ethyl acetate. The organic layers were combined and washed with100 mL water, 30 mL brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give 1.04 g of a yellow crudeoil. The crude product was a mixture of the two diastereomersN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine andN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanamine.

EXAMPLE 15 ##STR40## Preparation of 3S-N-(t-Butoxycarbonyl)-N-(Dhenylmethyl)amino!-1-(2-methylpropyl)amino-4-phenylbutan-2R-ol

To a solution of 500 mg (1.42 mmoles) of the crude epoxide (a mixture ofthe two diastereomers N,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine andN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanamine in0.98 mL of isopropanol was added 0.71 mL (7.14 mmoles) of isobutylamine.The mixture was warmed to reflux at 85° C. to 90° C. for 1.5 hours. Themixture was concentrated under reduced pressure and the product oil waspurified by silica gel chromatography (chloroform:methanol, 100:6 aseluting solvents) to give 330 mg of 3S-N-(t-butoxycarbonyl)-N-(phenylmethyl)amino!-1-(2-methylpropyl)amino-4-phenylbutan-2R-ol as a colorless oil(54.5% yield). 3S-N-(t-Butoxycarbonyl)-N-(phenylmethyl)amino!-1-(2-methylpropyl)amino-4-phenylbutan-2S-ol was also isolated. When purifiedN,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxirane methanamine wasused as starting material, 3S- N-(t-butoxycarbonyl)-N-(phenylmethyl)amino!-1-(2-methylpropyl)amino-4-phenylbutan-2R-ol was isolated afterpurification by chromatography in an 86% yield.

EXAMPLE 16 ##STR41## Preparation of 3S-(N-t-Butoxycarbonyl)amino-4-phenylbutan-1,2R-diol

To a solution of 1 g (3.39 mmoles) of2S-(N-t-butoxycarbonyl)amino-1S-hydroxy-3-phenylbutanoic acid(commercially available from Nippon Kayaku, Japan) in 50 mL of THF at 0°C. was added 50 mL of borane-THF complex (liquid, 1.0M in THF), keepingthe temperatures below 5° C. The reaction mixture was warmed to roomtemperature and stirred for 16 hours. The mixture was cooled to 0° C.and 20 mL of water was added slowly to destroy the excess BH₃ and toquench the product mixture, keeping the temperature below 12° C. Thequenched mixture was stirred for 20 minutes and concentrated underreduced pressure. The product mixture was extracted three times with 60mL of ethyl acetate. The organic layers were combined and washed with 20mL of water, 25 mL of saturated sodium chloride solution andconcentrated under reduced pressure to give 1.1 g of crude oil. Thecrude product was purified by silica gel chromatography(chloroform/methanol, 10:6 as eluting solvents) to give 900 mg (94.4%yield) of 3S-(N-t-butoxycarbonyl)amino-4-phenylbutan-1,2R-diol as awhite solid.

EXAMPLE 17 ##STR42## Preparation of 3S-(N-t-Butoxycarbonyl)amino-2R-hydroxy-4-phenylbut-1-yl Toluenesulfonate

To a solution of 744.8 mg (2.65 mmoles) of3S-(N-t-butoxycarbonyl)amino-4-phenylbutan-1,2R-diol in 13 mL ofpyridine at 0° C. was added 914 mg of toluenesulfonyl chloride in oneportion. The mixture was stirred at 0° C. to 5° C. for 5 hours. Amixture of 6.5 mL of ethyl acetate and 15 mL of 5% aqueous sodiumbicarbonate solution was added to the reaction mixture and stirred for 5minutes. The product mixture was extracted three times with 50 mL ofethyl acetate. The organic layers were combined and washed with 15 mL ofwater, 10 mL of saturated sodium chloride solution and concentratedunder reduced pressure to give about 1.1 g of a yellow chunky solid. Thecrude product was purified by silica gel chromatography (ethylacetate/hexane 1:3 as eluting solvents) to give 850 mg (74% yield) of3S-(N-t-butoxycarbonyl)amino-2R-hydroxy-4-phenylbut-1-yltoluenesulfonate as a white solid.

EXAMPLE 18 ##STR43## Preparation of 3S-N-(t-Butoxycarbonyl)amino!-1-(2-methylpropyl) amino-4-phenylbutan-2R-ol

To a solution of 90 mg (0.207 mmoles) of 3S-(N-t-butoxycarbonyl)amino-2R-hydroxy-4-phenylbut-1-yl toluenesulfonate in 0.143 mL ofisopropanol and 0.5 mL of toluene was added 0.103 mL (1.034 mmoles) ofisobutylamine. The mixture was warmed to 80° to 85° C. and stirred for1.5 hours. The product mixture was concentrated under reduced pressureat 40° to 50° C. and purified by silica gel chromatography(chloroform/methanol, 10:1 as eluting solvents) to give 54.9 mg (76.8%yield) of 3S- N-(t-butoxycarbonyl)amino!-1-(2-methylpropyl)amino-4-phenylbutan-2R-ol as a white solid.

EXAMPLE 19 Preparation of N-3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl!-N-isoamylamine##STR44## Part A:

To a solution of 75.0 g (0.226 mol) of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of 807 mL ofmethanol and 807 mL of tetrahydrofuran at -2° C., was added 13.17 g(0.348 mol, 1.54 equiv.) of solid sodium borohydride over one hundredminutes. The solvents were removed under reduced pressure at 40° C. andthe residue dissolved in ethyl acetate (approx. 1 L). The solution waswashed sequentially with 1M potassium hydrogen sulfate, saturated sodiumbicarbonate and then saturated sodium chloride solutions. After dryingover anhydrous magnesium sulfate and filtering, the solution was removedunder reduced pressure. To the resulting oil was added hexane (approx. 1L) and the mixture warmed to 60° C. with swirling. After cooling to roomtemperature, the solids were collected and washed with 2 L of hexane.The resulting solid was recrystallized from hot ethyl acetate and hexaneto afford 32.3 g (43% yield) ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150°-151° C. and M+Li⁺ =340.

Part B:

To a solution of 6.52 g (0.116 mol, 1.2 equiv.) of potassium hydroxidein 968 mL of absolute ethanol at room temperature, was added 32.3 g(0.097 mol) of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol. Afterstirring for fifteen minutes, the solvent was removed in vacuo. Theresidue was dissolved in methylene chloride, washed with water, dried(magnesium sulfate), filtered and stripped to yield 27.9 g of a whitesolid. Recrystallization from hot ethyl acetate and hexane afforded 22.3g (77% yield) ofN-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane, mp 102°-103°C. and MH⁺ 298.

Part C:

A solution of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (1.00 g, 3.36 mmol) andisoamylamine (4.90 g, 67.2 mmol, 20 equiv.) in 10 mL of isopropylalcohol was heated to reflux for 1.5 hours. The solution was cooled toroom temperature, concentrated in vacuo and then poured into 100 mL ofstirring hexane whereupon the product crystallized from solution. Theproduct was isolated by filtration and air dried to give 1.18 g, 95% ofN= 3(S)-phenylmethylcarbamoyl)amino-2(R)-hydroxy-4-phenylbutyl!N-(3-methylbutyl)!amine mp 108.0°-109.5° C., MH⁺ m/z=371.

EXAMPLE 20 ##STR45## Preparation of phenylmethyl 2R-hydroxy-3-(3-methylbutyl) (phenylsulfonyl)amino!-1S-(phenylmethyl)propyl!carbamate

From the reaction of N-3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl!isoamylamine(1.47 gm, 3.8 mmol), triethylamine (528 uL, 3.8 mmol) and benzenesulfonyl chloride (483 uL, 3.8 mmol) one obtains benzyl 2R-hydroxy-3-(3-methylbutyl)(phenylsulfonyl)amino!-1S-(phenylmethyl)propyl!carbamate.Column chromotography on silica gel eluting with chloroform containing1% ethanol afforded the pure product. Anal. Calcd for C₂₉ H₃₆ N₂ O₅ S:C, 66.39; H, 6.92; N, 5.34. Found: C, 66.37; H, 6.93; N, 5.26.

EXAMPLE 21 ##STR46## Preparation of 2R-hydroxy-3-(4-aminophenyl)sulfonyl!(2-methylpropyl)amino!-1S(phenylmethyl)propylamine

Part A: Preparation of Carbamic acid, 2R-hydroxy-3- (4-nitrophenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl) propyl-, phenylmethylester

To a solution of 4.0 g (10.8 mmol) of N- 3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl!-N-isobutylamine in 5 mL of anhydrousmethylene chloride, was added 4.5 mL (3.27 g, 32.4 mmol) oftriethylamine. The solution was cooled to 0° C. and 2.63 g (11.9 mmol)of 4-nitrobenzene sulfonyl chloride was added, stirred for 30 minutes at0° C., then for 1 hour at room temperature. Ethyl acetate was added,washed with 5% citric acid, saturated sodium bicarbonate, brine, driedand concentrated to yield 5.9 g of crude material. This wasrecrystallized from ethyl acetate/hexane to afford 4.7 g of purecarbamic acid, 2R-hydroxy-3- (4-nitrophenyl) sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propyl-, phenylmethyl ester, m/e=556(M+H).

Part B: Preparation of 2R-hydroxy-3- (4-aminophenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl) propylamine

A solution of 3.0 g (5.4 mmol) of carbamic acid, 2R-hydroxy-3-(4-nitrophenyl) sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propyl-, phenylmethyl ester in 20 mL of ethylacetate was hydrogenated over 1.5 g of 10% palladium-on-carbon catalystunder 35 psig of hydrogen for 3.5 hours. The catalyst was removed byfiltration and the solution concentrated to afford 2.05 g of the desired2R-hydroxy-3- (4-aminophenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylamine, m/e=392(M+H).

EXAMPLE 22 ##STR47## Preparation of 2R-hydroxy-3-(3-aminophenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylamine

Part A: Preparation of Carbamic acid, 2R-hydroxy-3-(3-nitrophenylsulfonyl) (2-methylpropyl)amino!-1S-(phenylmethyl)propyl-,phenylmethyl ester

To a solution of 1.1 g (3.0 mmol) of N- 3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl!-N-isobutylamine in 15 mL of anhydrousmethylene chloride, was added 1.3 mL (0.94 g, 9.3 mmol) oftriethylamine. The solution was cooled to 0° C. and 0.67 g (3.0 mmol) of3-nitrobenzene sulfonyl chloride was added, stirred for 30 minutes at 0°C., then for 1 hour at room temperature. Ethyl acetate was added, washedwith 5% citric acid, saturated sodium bicarbonate, brine, dried andconcentrated to yield 1.74 g of crude material. This was recrystallizedfrom ethyl acetate/hexane to afford 1.40 g of pure carbamic acid,2R-hydroxy-3- (3-nitrophenylsulfonyl)(2-methylpropyl)amino!-1S-(phenylmethyl)propyl-, phenylmethyl ester, m/e=562(M+Li).

Part B: Preparation of 2R-hydroxy-3- (3-aminophenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylamine

A solution of 1.33 g (2.5 mmol) of carbamic acid, 2R-hydroxy-3-(3-nitrophenylsulfonyl) (2-methylpropyl)amino!-1S-(phenylmethyl)propyl-, phenylmethyl ester in 40 mL of 1:1 methanol/tetrahydrofuran washydrogenated over 0.70 g of 10% palladium-on-carbon catalyst under 40psig of hydrogen for 1.5 hours. The catalyst was removed by filtrationand the solution concentrated to afford 0.87 g of the desired2R-hydroxy-3-(3-aminophenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylamine.

EXAMPLE 23 ##STR48## Preparation of 2R-hydroxy-3-(2,3-dihydrobenzofuran-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylamine

Part A: Preparation of 5-(2,3-dihydrobenzofuranyl) sulfonyl chloride

To a solution of 3.35 g of anhydrous N,N-dimethylformamide at 0° C.under nitrogen was added 6.18 g of sulfuryl chloride, whereupon a solidformed. After stirring for 15 minutes, 4.69 g of 2,3-dihydrobenzofuranwas added, and the mixture heated at 100° C. for 2 hours. The reactionwas cooled, poured into ice water, extracted with methylene chloride,dried over magnesium sulfate, filtered and concentrated the crudematerial. This was recrystallized from ethyl acetate to afford 2.45 g of5-(2,3-dihydrobenzofuranyl)sulfonyl chloride.

Part B: Preparation of Carbamic acid, 2R-hydroxy-3-(2,3-dihydrobenzofuran-5-yl) sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propyl-, phenylmethyl ester

To a solution of 1.11 g (3.0 mmol) of N- 3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl!-N-isobutylamine in 20 mL of anhydrousmethylene chloride, was added 1.3 mL (0.94 g, 9.3 mmol) oftriethylamine. The solution was cooled to 0° C. and 0.66 g of5-(2,3-dihydrobenzofuranyl) sulfonyl chloride was added, stirred for 15minutes at 0° C., then for 2 hour at room temperature. Ethyl acetate wasadded, washed with 5% citric acid, saturated sodium bicarbonate, brine,dried and concentrated to yield 1.62 g of crude material. This wasrecrystallized from diethyl ether to afford 1.17 g of pure carbamicacid, 2R-hydroxy-3-(2,3-dihydrobenzofuran-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propyl-, phenylmethyl ester.

Part C: Preparation of 2R-hydroxy-3- (2,3-dihydrobenzofuran-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylamine

A solution of 2.86 g of carbamic acid, 2R-hydroxy-3-(2,3-dihydrobenzofuran-5-yl) sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propyl-, phenylmethyl ester in 30 mL oftetrahydrofuran was hydrogenated 0.99 g of 10% palladium-on-carbon under50 psig of hydrogen for 16 hours. The catalyst was removed by filtrationand the filtrate concentrated to afford 1.99 g of the desired2R-hydroxy-3-(2,3-dihydrobenzofuran-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylamine.

EXAMPLE 24 ##STR49## Preparation of N- (1,1-dimethylethoxyl)carbonyl!-N-2-methylpropyl!-3S- N¹-(phenylmethoxycarbonyl)amino!-2R-hydroxy-4-phenylbutylamine

To a solution of 7.51 g (20.3 mmol) of N- 3S- (phenylmethoxycarbonyl)amino!-2R-hydroxy-4-phenylbutyl!-2-methylpropylamine in 67 mL ofanhydrous tetrahydrofuran was added 2.25 g (22.3 mmol) of triethylamine.After cooling to 0° C., 4.4 g (20.3 mmol) of di-tert-butyl dicarbonatewas added and stirring continued at room temperature for 21 hours. Thevolatiles were removed in vacuo, ethyl acetate added, then washed with5% citric acid, saturated sodium bicarbonate, brine, dried overmagnesium sulfate, filtered and concentrated to afford 9.6 g of crudeproduct. Chromatography on silica gel using 30% ethyl acetate/hexaneafforded 8.2 g of pure N-3S-(phenylmethylcarbamoyl)amino!-2R-hydroxy-4-phenyl!-1-(2-methylpropyl) amino-2-(1,1-dimethylethoxyl)carbonyl! butane, massspectum m/e=477(M+Li).

EXAMPLE 25 ##STR50## Preparation of 2-methyl-3-(2-phenylethyl)sulfonyl!propionic acid N-hydroxybenzotriazole ester

Part A: A solution of methyl methacrylate (7.25 g, 72.5 mmol) andphenethyl mercaptan (10.0 g, 72.5 mmol) in 100 mL of methanol was cooledin an ice bath and treated with sodium methoxide (100 mg, 1.85 mmol).The solution was stirred under nitrogen for 3 h and then concentrated invacuo to give an oil that was taken up in ether and washed with 1Naqueous potassium hydrogen sulfate, saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate, filtered and concentrated togive 16.83 g, 97.5% of methyl 2-(R,S)-methyl-4-thia-6-phenyl hexanoateas an oil. TLC on SiO₂ eluting with 20:1 hexane:ethyl acetate (v:v)R_(f) =0.41. Alternatively, one can use methyl 3-bromo-2-methylpropionate in place of methyl methacrylate.

Part B: A solution of methyl 2-(R,S)-methyl-4-thia-6-phenyl hexanoate(4.00 g, 16.8 mmol) in 100 mL of dichloromethane was stirred at roomtemperature and treated portion wise with meta-chloroperoxybenzoic acid(7.38 g, 39.2 mmol) over approximately 40 m. The solution was stirred atroom temperature for 16 h and then filtered and the filterate washedwith saturated aqueous sodium bicarbonate, 1N sodium hydroxide,saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated to give 4.50 g, 99% of desiredsulfone. The unpurified sulfone was dissolved in 100 mL oftetrahydrofuran and treated with a solution of lithium hydroxide (1.04g, 24.5 mmol) in 40 mL of water. The solution was stirred at roomtemperature for 2 m and then concentrated in vacuo. The residue was thenacidified with 1N aqueous potassium hydrogen sulfate to pH=1 and thenextracted three times with ethyl acetate. The combined ethyl acetatesolution was washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, filtered and concentrated to give a whitesolid. The solid was taken up in boiling ethyl acetate/hexane andallowed to stand undisturbed whereupon white needles formed that wereisolated by filtration and air dried to give 3.38 g, 79% of2-(R,S)-methyl-3(β-phenethylsulfonyl)-propionic acid, mp 91°-93° C.

Part C: A solution of 2-(R,S)-methyl-3(β-phenethylsulfonyl)-propionicacid (166.1 mg, 0.65 mmol), N-hydroxybenzotriazole (HOBT) (146.9 mg,0.97 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC) (145.8 mg, 0.75 mmol) in 4 mL of anhydrousdimethylformamide (DMF) cooled to 0° C. and stirred under nitrogen for0.5 h. This solution is then treated with a desired protected amino orsulfonamide isostere intermediate and stirred at room temperature for 16h. The solution is poured into 30 mL of 60% saturated aqueous sodiumbicarbonate solution. The aqueous solution is then decanted from theorganic residue. The organic residue is taken up in dichloromethane andwashed with 10% aqueous citric acid, brine, dried over anhydrousmagnesium sulfate, filtered and concentrated. Flash chromatography ofthe mixture on silica gel eluting with 1:1 hexane:ethyl acetate can beutilized and will afford the separated diastereomers.

EXAMPLE 26 ##STR51## Preparation of 2-methyl-3-(methylsulfonyl)propionicacid N-hydroxybenzotriazole ester

Part A: A solution of methyl 2-(bromomethyl)-acrylate (26.4 g, 0.148mol) in 100 mL of methanol was treated with sodium methanesulfinate(15.1 g, 0.148 mol) portion wise over 10 m at room temperature. Thesolution was then stirred at room temperature for a period of 1.25 h andthe solution concentrated in vacuo. The residue was then taken up inwater and extracted four times with ethyl acetate. The combined ethylacetate solution was washed with saturated sodium chloride, dried overanhydrous magnesium sulfate, filtered and concentrated to give a whitesolid, 20.7 g which was taken up in boiling acetone/methyl tert-butylether and allowed to stand whereupon crystals of pure methyl2-(methylsulfonylmethyl) acrylate 18.0 g, 68% formed, mp 65°-68° C.

Part B: A solution of methyl 2-(methylsulfonylmethyl) acrylate (970 mg,5.44 mmol) in 15 mL of tetrahydrofuran was treated with a solution oflithium hydroxide (270 mg, 6.4 mmol) in 7 mL of water. The solution wasstirred at room temperature for 5 m and then acidified to pH=1 with 1Naqueous potassium hydrogen sulfate and the solution extracted threetimes with ethyl acetate. The combined ethyl acetate solution was driedover anhydrous magnesium sulfate, filtered, and concentrated to give 793mg, 89% of 2-(methylsulfonylmethyl)acrylic acid, mp 147°-149° C.

Part C: A solution of 2-(methylsulfonylmethyl) acrylic acid (700 mg,4.26 mmol) in 20 mL of methanol was charged into a Fisher-Porter bottlealong with 10% palladium on carbon catalyst under a nitrogen atmosphere.The reaction vessel was sealed and flushed five times with nitrogen andthen five times with hydrogen. The pressure was maintained at 50 psigfor 16 h and then the hydrogen was replaced with nitrogen and thesolution filtered through a pad of celite to remove the catalyst and thefilterate concentrated in vacuo to give 682 mg 96% of2-(R,S)-methyl-3-methylsulfonyl propionic acid.

Part D: A solution of 2-(R,S)-methyl-3(methylsulfonyl) propionic acid(263.5 mg, 1.585 mmol), N-hydroxybenzotriazole (HOBT) (322.2 mg, 2.13mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC) (339.1 mg, 1.74 mmol) in 4 mL of anhydrous dimethylformamide (DMF)is cooled to 0° C. and stirred under nitrogen for 0.5 h. This solutionis then treated with a desired protected amino or sulfonamide isostereintermediate and stirred at room temperature for 16 h. The solution ispoured into 60 mL of 60% saturated aqueous sodium bicarbonate solution.The aqueous solution is then decanted from the organic residue. Theorganic residue is taken up in dichloromethane and washed with 10%aqueous citric acid, brine, dried over anhydrous magnesium sulfate,filtered and concentrated to give the desired product.

EXAMPLE 27 Preparation of Sulfone Inhibitors FromL-(+)-S-acetyl-β-mercaptoisobutyric Acid

Part A: A round-bottomed flask is charged with the desired protectedamino or sulfonamide isostere intermediate (2.575 mmol) and coupled toL-(+)-S-acetyl-b-mercapto butyric acid in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (339.1mg, 1.74 mmol), in 10 mL of CH₂ Cl₂ and is allowed to stir at roomtemperature for 16 h. The solution is concentrated in vacuo and theresidue taken up in ethyl acetate, washed with 1N KHSO₄ sat. aq. NaHCO₃,brine, dried over anhydrous MgSO₄, filtered and concentrated to give anoil which can be purified by radial chromatography on SiO₂ eluting withethyl acetate to give the pure product.

Part B: A solution of the product of Part A (0.85 mmol) in 10 mL ofmethanol is treated with anhydrous ammonia for ca. 1 m at 0° C. Thesolution is stirred at that temperature for 16 h and then concentratedin vacuo to give the desired product that can be used directly in thenext step without further purification.

Part C: A solution of the product of Part B (0.841 mmol) in 10 mL of drytoluene under nitrogen is treated in rapid succession with1,8-diazabicyclo 5.4.0!undec-7-ene, (DBU), (128.1 mg. 0.841 mmol) andiodomethane (119.0 mg, 0.841 mmol). After 0.5 h at room temperature thereaction is diluted with ethyl acetate washed with 1N KHSO₄, sat. aq.NaHCO₃, brine. After the solution is dried over anhydrous MgSO₄,filtered and concentrated in vacuo the desired product is obtained andcan be used directly in the next step.

Part D: A solution of the product of Part C (0.73 mmol) and sodiumperborate (500 mg, 3.25 mmol) in 30 mL of glacial acetic acid is warmedto 55° C. for 16 h. The solution is conentrated in vacuo and then theresidue is taken up in ethyl acetate, washed with water, sat. aq.NaHCO₃, brine, dried over anhydrous MgSO₄, filtered and concentrated togive the desired product.

General Procedure for Coupling Sulfonyl Compounds to Sulfonamides

A mixture of the sulfonyl alkanoyl compound (approximately 1 mmol),N-hydroxybenzotriazole (1.5 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.2mmol) is dissolved in a suitable solvent such as DMF and allowed toreact for about 30 min. at 0° C. A desired protected amino orsulfonamide isostere intermediate (1.05 mmol) is dissolved in DMF, addedto the above mixture and stirred at room temperature for a period oftime sufficient for the reaction to take place. The solution is thenpoured into saturated aqueous NaHCO₃ and extracted with, for example,ethyl acetate. The extracts are washed, dried, filtered andconcentrated. The resulting material is then crystallized from asuitable solvent or solvent mixture such as hexanes and ethyl acetate toproduce the product.

EXAMPLE 28 ##STR52## Prepnaration of 2(S)-methyl-3-(methylsulfonyl)propionic Acid Part A: To a solution of 10 g ofD-(-)-S-benzoyl-b-mercaptioisobutyric acid t-butyl ester in 20 mL ofmethanol was bubbled in gaseous ammonia at 0° C. The reaction wasallowed to then warm to room temperature, stirred overnight andconcentrated under reduced pressure. The resulting mixture of a solid(benzamide) and liquid was filtered to provide 5.21 g of a pale oilwhich then solidified. This was identified as2(S)-methyl-3-mercaptopropionic acid t-butyl ester.

Part B: To a solution of 5.21 g of 2(S)-methyl-3-mercaptopropionic acidt-butyl ester in 75 mL of toluene at 0° C. was added 4.50 g of1,8-diazabicyclo 5.40!undec-7-ene and 1.94 mL of methyl iodide. Afterstirring at room temperature for 2.5 hours, the volatiles were removed,ethyl acetate added, washed with dilute hydrochloric acid, water, brine,dried and concentrated to afford 2.82 g of a pale oil, identified as2(S)-methyl-3-(thiomethyl)propionic acid t-butyl ester.

Part C: To a solution of 2.82 g of 2(S)-methyl-3-(thiomethyl)propionicacid t-butyl ester in 50 mL of acetic acid was added 5.58 g of sodiumperborate and the mixture heated to 55° C. for 17 hours. The reactionwas poured into water, extracted with methylene chloride, washed withaqueous sodium bicarbonate, dried and concentrated to afford 2.68 g of2(S)-methyl-3-(methyl sulfonyl)propionic acid t-butyl ester as a whitesolid.

Part D: To 2.68 g of 2(S)-methyl-3-(methylsulfonyl)-propionic acidt-butyl ester was added 20 mL of 4N hydrochloric acid/dioxane and themixture stirred at room temperature for 19 hours. The solvent wasremoved under reduced pressure to afford 2.18 g of crude product, whichwas recrystallized from ethyl acetate/hexane to yield 1.44 g of2(S)-methyl-3-(methylsulfonyl)propionic acid as white crystals.

EXAMPLE 29 Preparation of 1S- 1R*(R*) ,2S*!!-N- 2-hydroxy-3-r(2-methylpropyl) (3,4-dimethoxyphenylsulfonyl)amino!-1-(phenylmethyl)propyl!-2-methyl-3-(methylsulfonyl)propanamide ##STR53## Part A: Asolution of N-benzyloxycarbonyl-3(S)-amino-1,2-(S)-epoxy-4-phenylbutane(50.0 g, 0.168 mol) and isobutylamine (246 g, 3.24 mol, 20 equivalents)in 650 mL of isopropyl alcohol was heated to reflux for 1.25 hours. Thesolution was cooled to room temperature, concentrated in vacuo and thenpoured into 1 L of stirring hexane whereupon the product crystallizedfrom solution. The product was isolated by filtration and air dried togive 57.56 g, 92% of N-3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl!N-isobutylamine, mp108.0°-109.5° C., MH+ m/z=371.

Part B: A solution of N-3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl!N-isobutylamine(1.5356 g, 4.14 mmol) and triethylamine (522 mg, 5.17 mmol) in 15 mL ofdichloromethane was treated with 3,4-dimethoxybenzenesulfonyl chloride(1.0087 g, 4.26 mmol) at room temperature for 14 h. The solvent wasremoved in vacuo and the residue taken up in ethyl acetate and thenwashed with 1N KHSO₄, saturated aqueous NaHCO₃, brine, dried over anhydMgSO₄, filtered and concentrated to give 2.147 g, 90.5%, of a whitesolid, mp 124°-127° C., HRFAB MS; M+Li; calc'd. for C₃₀ H₃₈ N₂ O₇ S+Li:577.2560. Found: 577.2604.

Part C: A solution of carbamic acid, product from Part B (513 mg, 0.90mmol) in 30 mL of methanol was stirred with 20 mg of palladium blackcatalyst and 10 mL of formic acid for 15 h at room temperature. Thecatalyst was removed by filtration through diatomaceous earth and thefiltrate concentrated in vacuo and the residue taken up in ethylacetate. The ethyl acetate solution was washed with saturated aqueousNaHCO₃, brine and dried over anhyd MgSO₄, filtered and concentrated invacuo to give a white solid, 386 mg, 98%, mp 123°-130° C., FAB MS; M+Li⁺=443, that was used directly in the next step without furtherpurification.

Part D: A mixture of 2(S)-methyl-3-methylsulfonyl propionic acid (128mg, 0.77 mmol), N-hydroxybenzotriazole (179.9 mg, 1.17 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (177.3mg, 0.92 mmol) was dissolved in 1.5 mL of dimethylformamide (DMF) andallowed to react for 30 min at 0° C. The amine from Part C (359 mg, 0.82mmol) dissolved in 1 mL of DMF was added to the above mixture andstirred at room temperature for 48 h. The solution was then poured into75 mL of saturated aqueous NaHCO₃ and extracted with ethyl acetate. Theethyl acetate extracts were washed with 5% aqueous citric acid,saturated aqueous NaHCO₃, brine, dried over anhyd MgSO₄, filtered andconcentrated to give a clear oil, 220 mg. The material was crystallizedfrom hexanes and ethyl acetate to give 178 mg, 40% of pure product withmp 130°-133° C. HRFAB MS;M+Li⁺ ; calc'd. for C₂₇ H₄₀ N₂ O₈ S₂ Li:591.2386. Found: 591.2396.

EXAMPLE 30 ##STR54## Preparation of 1S- 1R*(R*) ,2S*!!-N- 2-hydroxy-3-(3-methylbutyl)(4-aminophenylsulfonyl)amino!-1-(phenylmethyl)propyl!-2-methyl-3-(methylsulfonyl)propanamide

Part A: A solution ofN-benzyloxycarbonyl-3(S)-amino-1,2(S)epoxy-4-phenylbutane (11.54 g,38.81 mmol) and isoamylamine (66.90 g, 0.767 mol, 19.9 equivalents) in90 mL of isopropyl alcohol was heated to reflux for 3.1 h. The solutionwas cooled to room temperature and partially concentrated in vacuo andthe remaining solution poured into 200 mL of stirring hexanes whereuponthe product crystallized from solution. The product was isolated byfiltration and air dried to give 11.76 g, 79% of N-3(S)-phenylmethoxy)carbonyl)amino-2 (R) -hydroxy-4-phenylbutyl!N-(3-methylbutyl)!amine, mp 118°-122° C., FAB MS: MH⁺ =385.

Part B: A solution of N- 3(S)-(phenylmethoxycarbonyl)amino-2(R)-hydroxy-4-phenylbutyl!N- (3-methylbutyl)!amine (1.1812 g,3.07 mmol) and triethylamine (325.7 mg, 3.22 mmol) in 20 mL ofdichloromethane was treated with 4-nitrobenzensulfonyl chloride (767 mg,90% purity 3.11 mmol) at room temperature for 10 min. The solvent wasremoved in vacuo and the residue taken up in ethyl acetate and thenwashed with 1N KHSO₄, saturated aqueous NaHCO₃, brine, dried over anhydMgSO₄, filtered and concentrated to give 2.3230 g, of a tan solid, thatwas crystallized from ethyl acetate and petroleum ether to provide 870mg, 50%, mp 130°-132° C. of pure product, HRFAB MS; M+Li, calc'd. forC₂₉ H₃₅ N₃ O₇ SLi: 576.2316. Found: 576.2350.

Part C: A solution of product from Part B (574 mg, 1.01 mmol) in 40 mLof methanol, (the solution was not completely homogeneous), was treatedwith 70 mg of 10% palladium on carbon catalyst and hydrogenated at 42psig for 15 h at room temperature. The catalyst was removed byfiltration through diatomaceous earth and the filtrate concentrated invacuo to give a white solid that was crystallized from chloroform, mp123°-127° C., FAB MS; M+Li⁺ =412, 400 mg, 91%, that was used directly inthe next step without further purification.

Part D: A mixture of 2(S)-methyl-3-methylsulfonyl propionic acid (112.3mg, 0.675 mmol), N-hydroxybenzotriazole (159.1 mg, 1.04 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (147.8mg, 0.77 mmol) was dissolved in 1.0 mL of dimethylformamide (DMF) andallowed to react for 30 min at 0° C. The amine from Part C (261.9 mg,0.646 mmol) dissolved in 0.5 mL of DMF was added to the above mixtureand stirred at room temperature for 16.5 h. The solution was then pouredinto 75 mL of saturated aqueous NaHCO₃ and extracted with ethyl acetate.The ethyl acetate extracts were washed with 5% aqueous citric acid,saturated aqueous NaHCO₃, brine, dried over anhyd MgSO₄, filtered andconcentrated to give a white foam, 326.3 mg. The material was purifiedby flash chromatography over silica gel eluting with ethyl acetate toprovide 213.6 mg, 64% of pure product as a white foam, FAB MS; MH⁺ =554.

EXAMPLE 31 ##STR55## Preparation of Carbamic acid, 2R-hydroxy-3-(2-aminobenzothiazol-6-yl)sulfonyl!(2-methylpropoyl)aminol!-1S-(phenylmethyl)propyl-, phenylmethyl ester

Carbamic acid, 2R-hydroxy-3-(4-aminophenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propyl-,phenylmethyl ester 0.30 g (0.571 mmol) was added to a well mixed powderof anhydrous copper sulfate (1.20 g) and potassium thiocyanate (1.50 g)followed by dry methanol (6 mL) and the resulting black-brown suspensionwas heated at reflux for 2 hrs. The reaction mixture was filtered andthe filtrate was diluted with water (5 mL) and heated at reflux. Ethanolwas added to the reaction mixture, cooled and filtered. The filtrateupon concentration afforded a residue which was chromatographed (ethylacetate:hexane 80:20) to afford 0.26 g (78%) of the desired compound asa solid.

EXAMPLE 32 ##STR56## Preparation of Carbamic acid, 2R-hydroxy-3-(benzothiazol-6-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propyl-,phenylmethyl ester

Method 1:

Carbamic acid, 2R-hydroxy-3-(2-aminobenzothiazol-6-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propyl-, phenylmethyl ester (0.25 g, 0.429 mmol) was added to a solutionof isoamylnitrite (0.116 mL, 0.858 mmol) in dioxane (5 mL) and themixture was heated at 85°0 C. After the cessation of evolution ofnitrogen, the reaction mixture was concentrated and the residue waspurified by chromatography (hexane:ethyl acetate 5:3) to afford 0.130 g(53%) of the desired product as a solid.

Method 2:

Crude benzothiazole-6-sulfonyl chloride in ethyl acetate (100 mL) wasadded to N- 3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl!-N-isobutylamine (1.03 g, 2.78 mmol) followedby N-methylmorpholine (4 mL). After stirring at room temperature for 18hr., the reaction mixture was diluted with ethyl acetate (100 mL),washed with citric acid (5%, 100 mL), sodium bicarbonate (saturated, 100mL) and brine (100 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was chromatographed (silica gel, ethyl acetate: hexane 1:1) toafford 0.340 g (23%) of desired product.

EXAMPLE 33 ##STR57## Preparation of Carbamic acid, 2R-hydroxy-3-(2-aminobenzothiazol-5-yl)sulfonyl!(2-methylpropyl)aminol-1S-(phenylmethyl)propyl-,phenylmethyl ester; and Carbamic acid, 2R-hydroxy-3-(2-aminobenzothiazol-7-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propyl-,phenylmethyl ester

The carbamic acid, 2R-hydroxy-3- (3-aminophenylsulfonyl)(2-methylpropyl)amino!-1S-(phenylmethyl)propyl-, phenylmethyl ester 0.36g (0.685 mmol) was added to a well mixed powder of anhydrous coppersulfate (1.44 g) and potassium thiocyanate (1.80 g) followed by drymethanol (10 mL) and the rsulting black-brown suspension was heated atreflux for 2 hrs. The reaction mixture was filtered and the filtrate wasdiluted with water (5 mL) and heated at reflux. Ethanol was added to thereaction mixture, cooled and filtered. The filtrate upon concentrationafforded a rseidue which was chromatographed (ethyl acetate:hexane 1:1)to afford 0.18 g (45%) of the 7-isomer as a solid. Further elution ofthe column with (ethyl acetate:hexane 3:2) afforded 0.80 g (20%)afforded the 5-isomer as a solid.

EXAMPLE 34 ##STR58## Preparation of 3S-amino-1-N-(2-methylpropyl)-N-(4-methoxyphenylsulfonyl)amino!-4-phenyl-2R-butanol

Part A: N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol

To a solution of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone(75 g, 0.2 mol) in a mixture of 800 mL of methanol and 800 mL oftetrahydrofuran was added sodium borohydride (13.17 g, 0.348 mol, 1.54equiv.) over 100 min. The solution was stirred at room temperature for 2hours and then concentrated in vacuo. The residue was dissolved in 1000mL of ethyl acetate and washed with 1N KHSO₄, saturated aqueous NaHCO₃,saturated aqueous NaCl, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to give an oil. The crude product was dissolved in1000 mL of hexanes at 60° C. and allowed to cool to room temperaturewhere upon crystals formed that were isolated by filtration and washedwith copious amounts of hexanes. This solid was then recrystallized fromhot ethyl acetate and hexanes to provide 32.3 g 43% ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150°-151° C., FAB MS: MLi⁺ =340.

Part B: 3(S)- N-(benzyloxycarbonyl)amino!-1,2(S)-epoxy-4-phenylbutane

A solution of potassium hydroxide (6.52 g. 0.116 mol, 1.2 equiv.) in 970mL of absolute ethanol was treated withN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol (32.3 g,0.097 mol). This solution was stirred at room temperature for 15 minutesand then concentrated in vacuo to give a white solid. The solid wasdissolved in dichloromethane and washed with water, dried over anhydMgSO₄, filetered and concentrated in vacuo to give a white solid. Thesolid was crystallized from hexanes and ethyl acetate to give 22.3 g,77% of 3(S)- N-(benzyloxycarbonyl) amino!-1,2(S)-epoxy-4-phenylbutane,mp 102°-103° C., FAB MS: MH⁺ 32 298.

Part C: N-3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl!N-isobutylamine

A solution of N-benzylcarbonyl-3(S)-amino-1,2-(S)-epoxy-4-phenyl butane(50.0 g, 0.168 mol) and isobutylamine (246 g, 3.24 mol, 20 equivalents)in 650 mL of isopropyl alcohol was heated to reflux for 1.25 hours. Thesolution was cooled to room temperature, concentrated in vacuo and thenpoured into 1 L of stirring hexane whereupon the product crystallizedfrom solution. The product was isolated by filtration and air dried togive 57.56 g, 92% of N3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl!-N-isobutylamine, mp108.0°-109.5° C., MH+m/z=371.

Part D: phenylmethyl 2(R)-hydroxy-3-N-(2-methylpropyl)-N-(4-methoxyphenylsulfonyl)amino!-1S-(phenylmethyl)propyl!carbamate

The amine from Part C (936.5 mg, 2.53 mmol) and triethylamine (2.88.5mg, 2.85 mmol) was dissolved in 20 mL of dichloromethane and treatedwith 4-methoxybenzenesulfonyl chloride (461 mg, 2.61 mmol). The solutionwas stirred at room temperature for 16 hours and then concentrated invacuo. The residue was dissolved in ethyl acetate and this solution waswashed with 1N KHSO₄, saturated aqueous NaHCO₃, brine, dried over anhydMgSO₄, filtered, and concentrated to give a clear oil 1.234 g. The oilwas crystallized from a mixture of ether and hexanes, 729.3 mg, 56.5% mp95°-99° C., FAB MS: MH⁺ =511.

Part E: 3S-amino-1-N-(2-methylpropyl)-N-(4-methoxyphenylsulfonyl)amino!-4-phenyl-2R-butanol

A solution of phenylmethyl 2(R)-hydroxy-3-N-(2-methylpropyl)-N-(4-methoxyphenylsulfonyl)amino!1-S-(phenylmethyl)propyl carbamate (671.1 mg, 1.31 mmol) from Part D in 10 mL of methanolwas hydrogenated over 50 mg of 10% palladium on carbon at 40 psig atroom temperature for 15 hours. The catalyst was removed by filtrationthrough diatomaceous earth and the filtrate concentrated to give a whitefoam, 474.5 mg, 96%, FAB MS: MH⁺ =377.

EXAMPLE 35 ##STR59## Preparation of 1,3-benzodioxole-5-sulfonyl chloride

Method 1:

To a solution of 4.25 g of anhydrous N,N-dimethylformamide at 0° C.under nitrogen was added 7.84 g of sulfuryl chloride, whereupon a solidformed. After stirring for 15 minutes, 6.45 g of 1,3-benzodioxole wasadded, and the mixture heated at 100° C. for 2 hours. The reaction wascooled, poured into ice water, extracted with methylene chloride, driedover magnesium sulfate, filtered and concentrated to give 7.32 g ofcrude material as a black oil. This was chromatographed on silica gelusing 20% methylene chloride/hexane to afford 1.9 g of(1,3-benzodioxol-5-yl)sulfonyl chloride.

Method 2:

To a 22 liter round bottom flask fitted with a mechanical stirrer, acooling condenser, a heating mantle and a pressure equalizing droppingfunnel was added sulfur trioxide DMF complex (2778 g, 18.1 moles).Dichloroethane (4 liters) was then added and stirring initiated.1,3-Benzodioxole (1905 g, 15.6 moles) as then added through the droppingfunnel over a five minute period. The temperature was then raised to 75°C. and held for 22 hours (NMR indicated that the reaction was done after9 hours.) The reaction was cooled to 26° and oxalyl chloride (2290 g,18.1 moles) was added at a rate so as to maintain the temperature below40° C. (1.5 hours). The mixture was heated to 67° C. for 5 hoursfollowed by cooling to 16° C. with an ice bath. The reaction wasquenched with water (5 l) at a rate which kept the temperature below 20°C. After the addition of water was complete, the mixture was stirred for10 minutes. The layers were separated and the organic layer was washedagain twice with water (5 l). The organic layer was dried with magnesiumsulfate (500 g) and filtered to remove the drying agent. The solvent wasremoved under vacuum at 50° C. The resulting warm liquid was allowed tocool at which time a solid began to form. After one hour, the solid waswashed with hexane (400 mL), filtered and dried to provide the desiredsulfonyl chloride (2823 g). The hexane wash was concentrated and theresulting solid washed with 400 mL hexane to provide additional sulfonylchloride (464 g). The total yield was 3287 g (95.5% based upon1,3-benzodioxole).

Method 3:

1,4-benzodioxan-6-sulfonyl chloride was prepared according to theprocedure disclosed in EP 583960, incorporated herein by reference.

EXAMPLE 36 ##STR60## Preparation of 1 N-(1,3-benzodioxol-5-yl)sulfonyl!-N-(2-methylpropyl)amino!-3(S)-bis(phenylmethyl)amino!-4-phenyl-2(R)-butanol

Method 1:

To a 5000 mL, 3-necked flask fitted with a mechanical stirrer was addedN- 3(S)-N,N-bis(phenylmethyl)amino!-2(R)-hydroxy-4-phenylbutyl!-N-isobutylamine•oxalicacid salt (354.7 g, 0.7 mole) and 1,4-dioxane (2000 mL). A solution ofpotassium carbonate (241.9 g, 1.75 moles) in water (250 mL) was thenadded. The resultant heterogeneous mixture was stirred for 2 hours atroom temperature followed by the addition of 1,3-benzodioxole-5-sulfonylchloride (162.2 g, 0.735 mole) dissolved in 1,4-dioxane (250 mL) over 15minutes. The reaction mixture was stirred at room temperature for 18hours. Ethyl acetate (1000 mL) and water (500 mL) were charged to thereactor and stirring continued for another 1 hour. The aqueous layer wasseparated and further extracted with ethyl acetate (200 mL). Thecombined ethyl acetate layers were washed with 25% brine solution (500mL) and dried over anhydrous magnesium sulfate. After filtering andwashing the magnesium sulfate with ethyl acetate (200 mL), the solventin the filtrate was removed under reduced pressure yielding the desiredsulfonamide as an viscous yellow foamy oil (440.2 g 105% yield). HPLC/MS(electrospray) (m/z 601 M+H!⁺ !.

EXAMPLE 37 Preparation of 1- N-(1,3-benzodioxol-5-yl)sulfonyl!-N-(2-methylpropyl)aminol-3(S)-amino-4-phenyl-2(R)-butanol•methanesulfonic acid salt ##STR61##Method 1:

Crude 1- N-(1,3-benzodioxol-5-yl)sulfonyl!-N-(2-methylpropyl)amino!-3(S)-bis(phenylmethyl)amino!-4-phenyl-2(R)-butanol (6.2 g, 0.010 moles) wasdissolved in methanol (40 mL). Methanesulfonic acid (0.969 g, 0.010moles) and water (5 mL) were then added to the solution. The mixture wasplaced in a 500 mL Parr hydrogenation bottle containing 20% Pd(OH)₂ oncarbon (255 mg, 50% water content). The bottle was placed in thehydrogenator and purged 5 times with nitrogen and 5 times with hydrogen.The reaction was allowed to proceed at 35° C. with 63 PSI hydrogenpressure for 18 hours. Additional catalyst (125 mg) was added and, afterpurging, the hydrogenation continued for and additional 20 hours. Themixture was filtered through celite which was washed with methanol (2×10mL). Approximately one third of the methanol was removed under reducedpressure. The remaining methanol was removed by aziotropic distillationwith toluene at 80 torr. Toluene was added in 15, 10, 10 and 10 mLportions. The product crystallized from the mixture and was filtered andwashed twice with 10 mL portions of toluene. The solid was dried at roomtemperature at 1 torr for 6 hours to yield the amine salt (4.5 g, 84%).HPLC/MS (electrospray) was consistent with the desired product (m/z 421M+H!⁺).

Method 2:

Part A: N- 3(S)-N,N-bis(phenylmethyl)amino!-2(R)-hydroxy-4-phenylbutyl!-N-isobutylamine•oxalicacid salt (2800 g, 5.53 moles) and THF (4 L) were added to a 22 L roundbottom flask fitted with a mechanical stirrer. Potassium carbonate (1921g, 13.9 moles) was dissolved in water (2.8 L) and added to the THFslurry. The mixture was then stirred for one hour.1,3-benzodioxole-5-sulfonyl chloride (1281 g, 5.8 moles) was dissolvedin THF (1.4 L) and added to the reaction mixture over 25 minutes. Anadditional 200 mL of THF was used to rinse the addition funnel. Thereaction was allowed to stir for 14 hours and then water (4 L) wasadded. This mixture was stirred for 30 minutes and the layers allowed toseparate. The layers was removed and the aqueous layer washed twice withTHF (500 mL). The combined THF layers were dried with magnesium sulfate(500 g) for one hour. This solution was then filtered to remove thedrying agent and used in subsequent reactions.

Part B: To the THF solution of crude 1- N-(1,3-benzodioxol-5-yl)sulfonyl!-N-(2-methylpropyl)amino!-3(S)-bis(phenylmethyl)amino!-4-phenyl-2(R)-butanol was added water (500 mL)followed by methane sulfonic acid (531 g, 5.5 moles). The solution wasstirred to insure complete mixing and added to a 5 gallon autoclave.Pearlman's catalyst (200 g of 20% Pd(OH)₂ on C/ 50% water) was added tothe autoclave with the aid of THF (500 mL). The reactor was purged fourtimes with nitrogen and four times with hydrogen. The reactor wascharged with 60 psig of hydrogen and stirring at 450 rpm started. After16 hours, HPLC analysis indicated that a small amount of the mono-benzylintermediate was still present. Additional catalyst (50 g) was added andthe reaction was allowed to run overnight. The solution was thenfiltered through celite (500 g) to remove the catalyst and concentratedunder vacuum in five portions. To each portion, toluene (500 mL) wasadded and removed under vacuum to azeotropically removed residual water.The resulting solid was divided into three portions and each washed withmethyl t-butyl ether (2 L) and filtered. The residual solvent wasremoved at room temperature in a vacuum oven at less than 1 torr toyield the 2714 g of the expected salt.

If desired, the product can be further purified by the followingprocedure. A total of 500 mL of methanol and 170 g of material fromabove was heated to reflux until it all dissolved. The solution wascooled, 200 mL of isopropanol added and then 1000-1300 mL of hexane,whereupon a white solid precipitated. After cooling to 0° C., thisprecipitate was collected and washed with hexane to afford 123 g of thedesired material. Through this procedure, the original material whichwas a 95:5 mixture of alcohol diastereomers was greater than 99:1 of thedesired diastereomer.

EXAMPLE 38 ##STR62## Preparation of 2R-hydroxy-3-(1,3-benzodioxol-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylamine

Part A: Preparation of 2R-hydroxy-3-(1,3-benzodioxol-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylcarbamic acid phenylmethyl ester

To a solution of 3.19 g (8.6 mmol) of N- 3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl!-N-isobutylamine in 40 mL of anhydrousmethylene chloride, was added 0.87 g of triethylamine. The solution wascooled to 0° C. and 1.90 g of (1,3-benzodioxol-5-yl)sulfonyl chloridewas added, stirred for 15 minutes at 0° C., then for 17 hours at roomtemperature. Ethyl acetate was added, washed with 5% citric acid,saturated sodium bicarbonate, brine, dried and concentrated to yieldcrude material. This was recrystallized from diethyl ether/hexane toafford 4.77 g of pure 2R-hydroxy-3-(1,3-benzodioxol-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylcarbamicacid phenylmethyl ester.

Part B: Preparation of 2R-hydroxy-3-(1,3-benzodioxol-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylamine

A solution of 4.11 g of carbamic acid, 2R-hydroxy-3-(1,3-benzodioxol-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propyl-,phenylmethyl ester in 45 mL of tetrahydrofuran and 25 mL of methanol washydrogenated over 1.1 g of 10% palladium-on-carbon under 50 psig ofhydrogen for 16 hours. The catalyst was removed by filtration and thefiltrate concentrated to afford 1.82 g of the desired 2R-hydroxy-3-(1,3-benzodioxol-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylamine.

EXAMPLE 39 ##STR63## Preparation of Benzothiazole-6-sulfonyl Chloride

Part A: Preparation of N-(4-Sulfonamidophenyl)thiourea

A mixture of sulfanilamide (86 g, 0.5 mole), ammonium thiocyanate (76.0g, 0.5 mole) and dilute hydrochloric acid (1.5N, 1 L) was mechanicallystirred and heated at reflux for 2 hr. About 200 mL of water wasdistilled off and concentration of the reaction mixture afforded asolid. The solid was filtered and was washed with cold water and airdried to afford 67.5 g (59%) of the desired product as a white powder.

Part B: Preparation of 2-Amino-6-sulfonamidobenzothiazole

Bromine (43.20 g, 0.27 mol) in chloroform (200 mL) was added over 1 hr.to a suspension of N-(4-sulfonamidophenyl)thiourea (27.72, 0.120 mol) inchloroform (800 mL). After the addition, the reaction mixture was heatedat reflux for 4.5 hr. The chloroform was removed in vacuo and theresidue was repeatedly distilled with additional amounts of chloroform.The solid obtained was treated with water (600 mL) followed by ammoniumhydroxide (to make it basic), then was heated at reflux for 1 hr. Thecooled reaction mixture was filtered, washed with water and air dried toafford 22.0 g (80%) of the desired product as a white powder.

Part C: Preparation of Benzothiazole-6-sulfonic acid

A suspension of 2-amino-6-sulfonamido-benzothiazole (10.0 g, 43.67 mmol)in dioxane (300 mL) was heated at reflux. Isoamylnitrite (24 mL) wasadded in two portions to the reaction mixture. Vigorous evolution of gaswas observed (the reaction was conducted behind a shield as aprecaution) and after 2 hr., a red precipitate was deposited in thereaction vessel. The reaction mixture was filtered hot, and the solidwas washed with dioxane and was dried. The solid was recrystallized frommethanol-water. A small amount of a precipitate was formed after 2 days.The precipitate was filtered off and the mother liquor was concentratedin vacuo to afford a pale red-orange solid (8.0 g, 85%) of pure product.

Part D: Preparation of 6-Chlorosulfonylbenzothiazole

Thionyl chloride (4 mL) was added to a suspension of thebenzothiazole-6-sulfonic acid (0.60 g, 2.79 mmol) in dichloroethane (15mL) and the reaction mixture was heated at reflux and dimethylformamide(5 mL) was added to the reaction mixture to yield a clear solution.After 1.5 hr. at reflux, the solvent was removed in vacuo and excess HCland thionyl chloride was chased by evaporation with dichloroethane.

EXAMPLE 40 Preparation of 2R-hydroxy-3- (1,4-benzodioxan-6-yl) sulfonyl(2-methylpropyl)amino!-1S-(phenylmethyl)propyl carbamic acidphenylmethyl ester ##STR64##

To a solution of the N- 3S- (phenylmethoxycarbonyl)amino!-2R-hydroxy-4-phenylbutyl!-N-(2-methylpropyl)amine (0.5 g, 1.35mmol) in CH₂ Cl₂ (5.0 mL) containing Et₃ N (0.35 mL, 2.5 mmol) was added1,4-benzodioxan-6-sulfonyl chloride (0.34 g, 1.45 mmol) and stirred at0° C. for 30 min. After stirring at room temperature for 1 hour, thereaction mixture was diluted with CH₂ Cl₂ (20 mL), washed with cold 1NHCl (3×20 mL), water (2×20 mL), satd. NaHCO₃ (2×20 mL) and water (3×20mL), dried (Na₂ SO₄) and concentrated under reduced pressure. Theresulting residue was purified by flash chromatography using 35% EtOAcin hexane to give the desired product as a white amorphous solid whichcrystallized from MeOH as a white powder (0.65 g. 84% yield): m. p.82°-84° C., HRMS-FAB : calcd for C₃₀ H₃₇ N₂ O₇ S 569.2321 (MH⁺), found569.2323.

EXAMPLE 41 Preparation of 2R-hydroxy-3-(benzothiazole-6-sulfonyl)-(2-methylpropyl)amino!-1S-(phenylmethyl)propylaminehydrochloride ##STR65## Part A: Preparation of 2R-hydroxy-3-(4-aminophenylsulfonyl)(2-methylpropyl)amino!-1S-(phenylmethyl)propylcarbamicacid t-butyl ester ##STR66## A mixture of 2R-hydroxy-3-(4-aminophenylsulfonyl)(2-methylpropyl)-amino!-1S-(phenylmethyl)propylamine3.7 g (9.45 mmol) and BOC-ON (2.33 g, 9.45 mmol) and triethylamine(0.954 g, 9.45 mmol) in tetrahydrofuran (60 mL) was stirred for 16 hoursand concentrated in vacuo. The residue was dissolved in dichloromethane(200 mL), washed with sodium hydroxide (1N, 100 mL) and citric acid (5%,100 mL), dried (MgSO4), and concentrated to afford 1.18 g (94%) of thedesired product as a white solid.

Part B: Preparation of 2R-Hydroxy-3-(2-aminobenzothiazol-6-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylcarbamicacid t-butyl ester ##STR67## The 2R-hydroxy-3-(4-aminophenylsulfonyl)(2-methylpropyl)amino!-1S-(phenylmethyl)propylcarbamicacid t-butyl ester (1.12 g, 2.279 mmol) was added to a well mixed powderof anhydrous copper sulfate (4.48 g) and potassium thiocyanate (5.60 g)followed by dry methanol (35 mL) and the resulting black-brownsuspension was heated at reflux for 2 hours. The reaction mixture turnedgrey. The reaction mixture was filtered and the filtrate was dilutedwith water (50 mL) and heated at reflux. Ethanol was added to thereaction mixture, cooled and filtered. The filtrate upon concentrationafforded a residue which was chromatographed (ethyl acetate:methanol90:10) to afford 0.80 g (78%) of the deprotected compound as a solid.This was directly reprotected via the following procedure; (2.25 g,5.005 mmol) BOC-ON (1.24 g), and triethylamine (0.505 g, 5.005 mmol) intetrahydrofuran (20 mL) was stirred at room temperature for 18 hours.The reaction mixture was concentrated and the residue was dissolved indichloromethane (200 mL) and was washed with sodium hydroxide (1N, 100mL) and citric acid (5%, 100 mL) dried (MgSO4) and concentrated toafford a residue which was chromatographed (ethyl acetate:hexane 3:1) toafford 1.8 g (65%) of the desired product as a solid.

Part C: Preparation of 2R-hydroxy-3-(benzothiazol-6-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylcarbamic acid t-butyl ester ##STR68## 2R-Hydroxy-3-(2-aminobenzothiazol-6-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylcarbamicacid t-butyl ester (1.80 g, 3.2755 mmol) was added to a solution ofisoamylnitrite (0.88 mL) in dioxane (20 mL) and the mixture was heatedat 85° C. After the cessation of evolution of nitrogen, the reactionmixture was concentrated and the residue was purified by chromatography(hexane:ethyl acetate 1:1) to afford 1.25 g (78%) of the desired productas a solid. Part D: Preparation of 2R-hydroxy-3-((benzothiazol-6-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylamine•hydrochloride. ##STR69## 2R-hydroxy-3-(benzothiazol-6-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylcarbamic acid t-butyl ester (1.25 g, 2.3385 mmol) was addeddioxane/HCl (4N, 10 mL) and was stirred at room temperature for 2 hoursand concentrated. Excess HCl was chased with toluene to afford 1.0 g(quantitative yield) of the desired product.

EXAMPLE 42 ##STR70## Preparation of2(S)-methyl-3-(methylsulfonyl)propionic Acid

Part A: To a solution of 200 g (1.23 mol) ofD-(-)-3-acetyl-b-mercaptoisobutyric acid in 1.0 L of methanol, was added161.0 g (2.47 mol) of potassium hydroxide dissolved in 500 mL ofmethanol while maintaining the temperature below 10° C. while coolingwith an ice bath. After stirring an additional 20 minutes, 117 mL (156g, 1.23 mol) of dimethyl sulfate was added while maintaining thetemperature below 20° C. The ice bath was removed and the mixturestirred for an additional 60 minutes. The salts were removed byfiltration, the solvents removed under reduced pressure and ethylacetate added. After separating the aqueous layer, it was acidified withconcentrated hydrochloric acid, extracted with ethyl acetate, dried overanhydrous magnesium sulfate, filtered and concentrated to afford 164 g(99%) of the desired 2S-methyl-3-(methylthio)propionic acid, m/e=133(M-H).

Part B: To a solution of 10.0 g (74.6 mmol) of2S-methyl-3-(methylthio)propionic acid in 150 mL of acetone and 30 mL ofwater, cooled to 18° C. in an ice bath, was added 161.8 g (263 mmol) ofOxone. After approximately half of material had been added, thetemperature rose to 24° C., the addition was stopped, temperaturelowered to 18° C., then addition continued. After stirring at 15°-20° C.for 15 minutes, the bath was removed and the reaction stirred at roomtemperature for 1 hour. The solids were filtered and washed withacetone, the filtrate concentrated to approximately 40 mL and theresidue dissolved in 200 mL of ethyl acetate. The ethyl acetate layerwas dried with anhydrous magnesium sulfate, filtered and concentrated toafford 11.4 g of an oil. This was dissolved in a minimum of ethylacetate and hexane added to cause a precipitate to form. This wascollected to afford 6.95 g of the desired product, m/e=167 (M+H).

EXAMPLE 43 ##STR71## Preparation of 1- (2-methylpropyl)(1,4-benzodioxane-6-yl)sulfonyl!amino!-3S-(phenylmethoxycarbonyl)aminol-4-phenylbutan-2R-o1

To a solution of the N- 3S- (phenylmethoxycarbonyl)amino!-2R-hydroxy-4-phenylbutyl!-N-(2-methylpropyl)amine (0.5 g, 1.35mmol) in CH₂ Cl₂ (5.0 mL) containing Et₃ N (0.35 mL, 2.5 mmol) was added1,4-benzodioxan-6-sulfonyl chloride (0.34 g, 1.45 mmol) (preparedaccording to the literature procedure in EP 583960 A2, 1994) and stirredat 0° C. for 30 min. After stirring at room temperature for 1h, thereaction mixture was diluted with CH₂ Cl₂ (20 mL), washed with cold 1NHCl (3×20 mL), water (2×20 mL), satd. NaHCO₃ (2×20 mL), water (3×20 mL),dried (Na₂ SO₄) and concentrated under reduced pressure. The resultingresidue was purified by flash chromatography using 35% EtOAc in hexaneto give the desired 1,4-benzodixan-sulfonamide as a white amorphoussolid which crystallized from MeOH as a white powder (0.65 g. 84%): m.p.82°-84° C., HRMS-FAB : calcd for C₃₀ H₃₇ N₂ O₇ S 569.2321 (MH⁺), found569.2323.

EXAMPLE 44 ##STR72## Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(methylsulfonyl)propanamide

Part A: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(acetylthio)propanamide ##STR73##N-Hydroxybenzotriazole (1.79 g, 11.6 mmol) was added to solutionD-(-)-S-acetyl-β-mercaptoisobutyric acid (1.26 g, 7.8 mmol) in 15 mL ofdry dimethylformamide and cooled in an ice bath. To the cooled solution,was added EDC (1.64 g, 8.5 mmol) and stirred for 30 minutes. To this wasadded (3.27 g, 7.8 mmol) of 2R-hydroxy-3-(1,3-benzodioxol-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylamineand this was stirred 16 hours with warming to room temperature. Thesolvent was removed and the residue partitioned between ethyl acetateand 5% aqueous potassium hydrogen sulfate. The organic layer was washedwith saturated sodium bicarbonate, and brine, dried over magnesiumsulfate filtered and concentrated to yield 4.4 grams of a crude oil,mass spectrum, m/z=571.8 (M+Li); HRMS: calcd for C₂₇ H₃₆ N₂ O₇ S₂565.2042, found 565.2028.

Part B: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide ##STR74## A solution of 4.29 g,(7.8 mmol) of S-acetyl compound from part A dissolved in 100 mL of drymethanol was cooled in an ice bath. Anhydrous ammonia was bubbled intothe solution for one minute. The solution was stoppered and stirred toroom temperature over 5 hours. The contents were concentrated on arotory evaporator, and the residue was dissolved in ethyl acetate. Theorganic solution was washed with water, and brine, dried over magnesiumsulfate, filtered and concentrated to yield 3.9 grams of the freemercaptan which was used without purification; mass spectrum, m/z=529.8(M+Li); HRMS: calcd for C₂₅ H₃₄ N₂ O₆ S₂ 523.1937, found 523.1942.

Part C: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(methylthio)propanamide ##STR75## A solution of 1.65g, (3.15 mmol) of the mercaptan from Part B in 25 mL of tetrahydrofuranwas cooled in an ice bath. To this cooled solution was added 0.52 g,3.52 mmol) of DBU followed by 0.22 mL, (3.5 mmoL) of methyl iodide andthe ice bath was removed after 5 minutes. After several hours at roomtemperature the contents were concentrated on a rotory evaporator, andthe residue was dissolved in ethyl acetate. The organics were washedwith potassium hydrogen sulfate, sodium bicarbonate and brine, driedover magnesium sulfate, filtered and concentrated to yield 1.48 g of acrude white foam.

Part D: Preparation of N- 2R-hyodroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(methylsulfonyl)propanamide

To a solution of 440 mg, (0.8 mmol) of thiomethylether from part C abovedissolved in 10 mL of methanol, was added 1.52 g, (24.0 mmol) of oxonefollowed by 10 mL of water. The suspension was stirred at roomtemperature for four hours. The mixture was concentrated on a rototryevaporator, diluted with 50 mL of water and extracted with ethylacetate. The organic layer was washed with sodium bicarbonate, driedover magnesium sulfate, filtered and concentrated to yield 390 mg ofcrude sulfone. Purification by flash chromatography using 1;1 ethylacetate ; hexane as the eluant yielded 330 mg of the desired compound;mass spectrum, m/z=575.4 (M+Li).

EXAMPLE 45 Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(methylsulfinyl)propanamide ##STR76## To a solutionof N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(methylthio)propanamide 1.04 g (1.94 mmoL) in 10 mLof glacial acetic acid was added 220 mg (1.94 mmoL) of 30% hydrogenperoxide with stirring. After one hour the reaction was stopped bydiluting with water and neutralization by the careful addition ofsaturated sodium bicarbonate. The resulting aqueous suspension wasextracted with ethyl acetate, and the organics were washed with 5%aqueous potassium hydrogen sulfate. The ethyl acetate layer was driedover magnesium sulfate, filtered, and concentrated to yield a mixture ofdiasteromeric sulfoxides. Separation of the two diastereomers by carefulflash chromatography yielded 250 mg of fast moving isomer 1, and 250 mgof slow moving isomer 2, and 400 mg of the mixture, mass spectrum,m/z=559.3 (M+Li) isomer 1, and m/z=559.3 isomer 2. EXAMPLE 46Preparation of 5-chlorosulfonyl-2-carbomethoxyamino-benzimidazole##STR77## A solution of 2-carbomethoxyamino-benzimidazole (5.0 g, 0.026mole) in chlorosulfonic acid (35.00 mL) was stirred at 0° C. for 30minutes and at room temperature for 3 hours. The resulting dark coloredreaction mixture was poured into an ice-water mixture (200 mL), andstirred at room temperature for 30 minutes. The resulting precipitatewas filtered and washed with cold water (500 mL). The solid was driedovernight under high vacuum in a desiccator over NaOH pellets to give5-chlorosulfonyl-2-carbomethoxyamino-benzimidazole (5.9 g, 78%) as agrey powder. ¹ H NMR (DMSO-d₆) d: 3.89 (s, 3H), 7.55 (d, J=8.4 Hz, 1H),7.65 (d, J=8.4 Hz, 1H), 7.88 (s, 1H). (German Patent DE 3826036) EXAMPLE47 Preparation of N- 2R-hydroxy-3- N¹ -(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl!-N¹-(2-methylpropyl)amino!-1S-(phenylmethyl)propyl!carbamic acidphenylmethyl ester ##STR78## To a cold solution of N- 3S-(phenylmethoxycarbonyl)amino!-2R-hydroxy-4-phenylbutyl!-N-(2-methylpropyl)amine (5.0 g, 13.5mmol) in dichloromethane (70 mL) was added triethylamine (5.95 g, 54.0mmol) followed by the addition of5-chlorosulfonyl-2-carbomethoxyamino-benzimidazole (4.29 g, 14.85 mmol)in small portions as a solid. The reaction mixture was stirred at 0° C.for 30 minutes and at room temperature for 2.5 hours when reaction ofthe amino alcohol was complete. The mixture was cooled and filtered, andthe filtrate was concentrated. The resulting residue was dissolved inEtOAc (200 mL), washed successively with cold 5% citric acid (3×50 mL),saturated aqueous sodium bicarbonate (3×50 mL) and water (3×100 mL),then dried (Na₂ SO₄), concentrated and dried under vacuum. The residuewas triturated with methanol, cooled, filtered, washed with MeOH-EtOAc(1:1, v/v) and dried in a desiccator to give pure N- 2R-hydroxy-3-(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl!(2-methylpropyl)-amino!-1S-(phenylmethyl)propyl!carbamic acid phenylmethyl ester (6.02 g, 72%) as a light brownpowder: FABMS: m/i=630 (M+Li); HRMS: calcd. for C₃₁ H₃₈ N₅ O₇ S (M+H)624.2492, found 624.2488. EXAMPLE 48

Preparation of 2R-hydroxy-3- (2-amino-benzimidazol-5-yl)sulfonyl!(2-methyl-propyl)amino!-1S-(phenylmethyl) propylamine ##STR79##A solution of N- 2R-hydroxy-3-(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propyl!carbamicacid phenylmethyl ester (0.36 g, 0.58 mmol) in 2.5 N methanolic KOH(2.00 mL) was heated at 70° C. under a nitrogen atmosphere for 3 hours.The reaction mixture was diluted with water (10 mL) and extracted withEtOAc (3×15 mL). The combined organic extracts were washed with brine,dried (Na₂ SO₄) and concentrated. The resulting residue was purified byreverse-phase HPLC using a 10-90% CH₃ CN/H₂ O gradient (30 min) at aflow rate of 70 mL/min. The appropriate fractions were combined andfreeze dried to give pure 2R-hydroxy-3-(2-amino-benzimidazol-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenyl-methyl)propylamine(0.22 g, 58%) as a white powder: FAB-MS m/z=432 (M+H); HRMS: calcd. forC₂₁ H₃₀ N₅ O₃ S (M+H) 432.2069, found 432.2071.

EXAMPLE 49 Preparation of N- 2R-hydroxy-3-(2-amino-benzimidazol-5-yl)sulfonyl!(2-methylpropyl)-amino!-1-(phenylmethyl)propyl!carbamic acid phenylmethyl ester ##STR80## To a solution of2R-hydroxy-3-(2-amino-benzimidazol-5-yl)sulfonyl!(2-methyl-propyl)amino!-1S-(phenylmethyl)propylamine (0.22 g, 0.33 mmol) in THF (3.00 mL), triethylamine (0.11 g,1.1 mmol) and benzyloxycarbonyl succinimide (0.09 g, 0.36 mmol) wereadded, and the reaction mixture was stirred at room temperature for 16hours. The solution was concentrated, and the residue was partitionedbetween EtOAc (15 mL) and saturated aqueous sodium bicarbonate. Theorganic phase was washed with brine, dried (Na₂ SO₄), and concentrated.The resulting residue was purified by reverse-phase HPLC using a 10-90%CH₃ CN/H₂ O gradient (30 min) at a flow rate of 70 mL/min. Theappropriate fractions were combined and freeze dried to give pure N-2R-hydroxy-3-(2-amino-benzimidazol-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propyl!carbamicacid phenylmethyl ester (0.12 g, 61%) as a white powder: FAB-MS m/z=566(M+H); HRMS: calcd. for C₂₉ H₃₆ N₅ O₅ S 566.2437 (M+H), found 566.2434.EXAMPLE 50 Preparation of 2R-hydroxy-3-(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylamine##STR81## A solution of N- 2R-hydroxy-3-(2-carbomethoxyamino-benzimidazole-5-yl)sulfonyl!(2-methylpropyl)-amino!-1S-(phenylmethyl)propyl!carbamicacid phenylmethyl ester (2.5 g, 0.4 mmol) in MeOH (10 mL) and THF (50mL) was hydrogenated in the presence of 10% Pd/C (1.2 g) at roomtemperature at 60 psi for 16 hours. The catalyst was removed byfiltration, and the filtrate was concentrated under reduced pressure.The resulting residue was triturated with ether and filtered. The solidsubstance thus obtained was washed with ether and dried in vacuo toafford pure 2R-hydroxy-3-(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)propylamine(1.5 g, 77%) as an off white powder: R_(t) =12.8 min; FAB-MS m/z=490(M+H); HRMS: calcd. for C₂₃ H₃₂ N₅ O₅ S 490.2124 (M+H), found 490.2142.EXAMPLE 51 ##STR82## Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(2-aminobenzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(methylsulfonyl)propanamide

To a solution of 2-(S)-methyl-3-methylsulfonyl propionic acid (0.249 g,1.5 mmol) in 5 mL of dry dimethylformamide, was added 1.5 equivalents ofN-hydroxy-benzotriazole, and the solution was cooled in an ice bath. Tothis cooled solution was added EDC (0.200 g, 1.5 mmol), and the solutionwas stirred for 30 minutes. To this was added 2R-hydroxy-3-(2-aminobenzothiazol-6-yl)sulfonyl!(2-methyl-propyl)amino!-1S-(phenylmethyl)propylamine (0.673 g, 1.5 mmol), and the reaction stirred for 16 hours.The contents were concentrated in vacuo and the residue was dissolved inethyl acetate, washed with 5% potassium hydrogen sulfate, saturatedsodium bicarbonate, and brine, dried over magnesium sulfate, filteredand concentrated to yield a crude oil. Purification by flash columnchromatograpy on silica gel using an eluant of 1:1:0.1 ethyl acetate:hexane:methanol yielded pure N- 2R-hydroxy-3- (2-methylpropyl)(2-amino-benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(methyl-sulfonyl)propanamide; FAB-MS: m/z=598.6(M+H).

EXAMPLE 52 Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(2-pyridyl)ethylsulfonyl)-propanamide ##STR83##Part A: Preparation of 2-(2-chloroethyl)pyridine•hydrochloride

2-(2-hydroxyethyl)pyridine (5 g, 41 mmol) was dissolved in 10 mL of1,2-dichloroethane, and thionyl chloride (9.67 g, 81 mmol) was addedslowly at room temperature. The reaction mixture was stirred for onehour at room temperature and was then concentrated at reduced pressure.Methylene chloride (20 mL) was twice added to the concentrated residueand then removed under reduced pressure. The resulting concentratedresidue was dried in vacuo to give 7.17 g (98.5%) of 2-(2-chloroethyl)pyridine•hydrochloride as a yellow solid: HRMS: calcd for C₇ H₈ N₁ Cl₁142.0424, found 142.0400.

Part B: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(2-pyridyl)ethylthio)propanamide

2-(2-chloroethyl)pyridine•hydrochloride (0.20 g, 1.15 mmol), potassiumbromide (0.28 g, 2.39 mmol) and a catalytic amount of 18 crown-6 weredissolved in 2.5 mL of N,N-dimethylacetamide (DMA) and stirred at roomtemperature for two hours. N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide(0.5 g, 0.96 mmol) and 1,8-diazabicyclo(5.4.0)-undec-7-ene (DBU, 0.44 g,2.87 mmol) were dissolved in 2.5 mL of DMA and added to this solution.The reaction mixture was stirred at room temperature for 24 hours, thenthe DMA was removed under vacuum. The residue was brought up in 150 mLof dichloromethane, and the organic solution was washed with 5% aqueousNaHCO₃ (2×100 mL), brine (2×100 mL), dried over MgSO4, filtered andconcentrated. The crude product was purified by flash chromatography onsilica gel eluting with 50:50 (v/v) ethylacetate:hexane to give 0.31 g(51.7%) of the desired sulfide product as a yellow gum: HRMS: calcd forC₃₂ H₄₁ N₃ O₆ S₂ 628.2515, found 628.2525.

Part C: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(2-pyridyl)ethylsulfonyl) propanamide

The sulfide product from Part B (0.25 g, 0.40 mmol) was dissolved in 9mL of methanol. Then oxone (0.74 g, 1.20 mmol) and 1.5 mL of water wereadded to the methanolic solution. The reaction mixture was stirred for4.5 hours at room temperature. The reaction mixture was cooled in an icebath, and 5% aqueous NaHCO₃ (10 mL) was added. The methanol was removedin vacuo, and the residue was brought up in 100 mL of dichloromethane.The dichloromethane solution was washed with (2×50 mL) 5% NaHCO₃, brine(2×50 mL), dried over MgSO4, filtered, and the filtered wasconcentrated, and dried in vacuo to give 0.12 g (45.6%) of the desiredsulfone as a white solid: HRMS: calcd for C₃₂ H₄₁ N₃ O₈ S₂ 660.2413,found 660.2421.

EXAMPLE 53 Preparation of N- 2R-hydroxy-3- (2-methyl-propyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- N-(2-(1-oxopyrrolidin-1-yl)ethyl)aminocarbonyl!methyl!sulfonyl!propoanamide ##STR84## Part A: Preparationof N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- N-(2-(1-pyrrolidinyl)ethyl)aminocarbonyl!methyl!thio!propanamide

1-(2-aminoethyl)pyrrolidine (0.11 g, 0.95 mmol), chloroacetic anhydride(0.16 g, 0.95 mmol) and triethylamine (96 mg, 0.95 mmol) were combinedwith 5 mL of methylene chloride at 5° C. in a 25 mL round bottom flask.The reaction mixture was warmed up to room temperature and then wasstirred at room temperature for one hour. The reaction mixture was thencooled in an ice-water bath to 5° C. N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide (0.50 g, 0.95 mmol) andtriethylamine (96 mg, 0.95 mmol) were dissolved in 5 mL of methylenechloride and added to the above solution such that the temperature didnot rise above 5° C. The reaction mixture was warmed to room temperatureand stirred at room temperature for two hours. Triethylamine (0.20 g,1.90 mmol) was added, and the reaction mixture was stirred overnight atroom temperature. The reaction mixture was diluted with 100 mL ofmethylene chloride. The organic solution was washed with saturatedaqueous NaHCO₃ (2×50 mL), brine (2×50 mL) and was dried over MgSO₄,filtered and concentrated at reduced pressure. The resulting residue waspurified by flash chromatography on silica gel eluting with 10% methanolin methylene chloride to give 0.28 g (43.5%) of the desired sulfideproduct as a pale yellow solid: HRMS: calcd for C₃₃ H₄₈ N₄ O₇ S₂677.3043, found 677.3051.

Part B: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- N-(2-(1-oxopyrrolidin-1-yl)ethyl)aminocarbonyl!methyl!sulfonyl!propanamide

The sulfide product from Part B (0.26 g, 0.38 mmol) was dissolved in 10mL of methanol. Then oxone (0.71 g, 1.15 mmol) and 2 mL of water wereadded to the methanolic solution. The reaction mixture was stirred fortwenty hours at room temperature, and the methanol was removed underreduced pressure. The concentrated residue was brought up in 100 mL ofmethylene chloride. The organic solution was washed with saturatedaqueous NaHCO₃ (2×50 mL), brine (2×50 mL), dried over MgSO₄, filteredand concentrated at reduced pressure. The concentrated residue waspurified by flash chromatography on silica gel eluting with a 15% to 25%methanol gradient in methylene chloride to give 0.1 g of the desiredsulfone as a pale yellow solid. The crude product was purified bypreparative reverse phase HPLC (30-90% acetonitrile in water containing0.1% trifluoroacetic acid) to give 35 mg (12.6%) of the desired puresulfone product as a pale yellow solid: HRMS: calcd for C₃₃ H₄₈ N.sub.O₁₀ S₂ 725.2890, found 725.2902.

EXAMPLE 54 ##STR85## Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-2-(4-(t-butoxycarbonyl)piperazin-1-ylcarbonyl)ethyl!sulfonyl!propanamide

Part A: Preparation of1-(3-chloropropionyl)-4-(t-butoxycarbonyl)piperazine

4-(t-butoxycarbonyl)piperazine (3 g, 16 mmol) was suspended in 10 mL ofmethylene chloride and cooled in an ice/water bath. 3-Chloropropionylchloride (2.04 g, 16 mmol) was dissolved in 10 mL of methylene chlorideand added slowly, while maintaining the internal temperature below 50°C. Triethylamine (1.63 g, 16 mmol) was then added to the cold (50° C.)solution. The solution was slowly warmed to room temperature and thenstirred at room temperature overnight. The reaction mixture was dilutedwith 150 mL of methylene chloride and washed with 5% aqueous NaHCO₃(2×100 mL), brine (2×100 mL), dried over MgSO₄, filtered, concentratedand dried under vacuum to give 3.71 g of crude product. The crudematerial was purified by flash chromatography on silica gel eluting withethyl acetate to give 1.85 g (41.8%) of1-(3-chloropropionyl)-4-(t-butoxycarbonyl)piperazine as a pale yellowsolid. ¹ H NMR (300 MHz/CDCl₃): δ 1.47 (s, 9H), 2.82 (t, 2H, J=6.95 Hz),3.40-3.46 (m, 6H), 3.60-3.63 (m, 2H), 3.84 (t, 2 H, J=6.95 Hz); massspectrum, m/z=283.1 (M+Li); high-resolution FAB-MS calcd for C₁₂ H₂₁ N₂O₃ Cl₁ 276.1240 (M+), found 276.1227.

Part B: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-2-(4-(t-butoxycarbonyl)piperazin-1-ylcarbonyl)ethyl!thio!propanamide

1-(3-Chloropropionyl)-4-(t-butoxycarbonyl)piperazine (0.38 g, 1.38mmol), potassium bromide (0.2 g, 1.72 mmol) and a catalytic amount of18-crown-6 were dissolved in 5 mL of N,N-dimethylacetamide (DMA) andstirred at room temperature for 2.5 hours. N- 2R-hydroxy-3-(2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide(0.6 g, 1.15 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (0.19 g, 1.26mmol) were dissolved in 5 mL of DMA and then added to the reactionmixture. The reaction mixture was stirred at room temperature for 18hours, and then the DMA was removed under vacuum. The residue wasbrought up in 150 mL of dichloromethane and washed with 5% aqueousNaHCO₃ (2×100 mL), brine (2×100 mL), dried over MgSO₄, filtered andconcentrated. The crude material was purified by flash chromatography onsilica gel eluting with 50:50 (v/v) ethyl acetate:hexane to give 0.34 g(38.7%) of the desired sulfide as a white foaming solid: HRMS: calcd forC₃₇ H₅₄ N₄ O₉ S₂ 763.3410, found 763.3437.

Part C: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-2-(4-(t-butoxycarbonyl)piperazin-1-ylcarbonyl)ethyl!sulfonyl!propanamide

The sulfide product from Part B (0.3 g, 0.39 mmol) was dissolved in 15mL of methanol. Then oxone (0.72 g, 1.18 mmol) and 3 mL of water wereadded to the methanolic solution. The reaction mixture was stirred for 5hours at room temperature, and the methanol was removed under vacuum.The resulting residue was brought up in 100 mL of dichloromethane. Thedichloromethane solution was washed with (2×50 mL) water, brine (2×50mL), dried over MgSO₄, filtered, and concentrated in vacuo to give 0.26g (83.9%) of the desired sulfone as a white solid: HRMS: calcd for C₃₇H₅₄ N₄ _(O) ₁₁ S₂ 795.3309, found 795.3312.

EXAMPLE 55 ##STR86## Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl) sulfonyl!amino!-1S-phenylmethyl)propyl!-2S-methl-3- 2-(piperazin-1-ylcarbonl)ethyl!sulfonyl!proppanamide•hydrochloride

N- 2R-Hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-2-(4-(t-butoxycarbonyl)piperazin-1-ylcarbonyl)ethyl!sulfonyl!propanamide(0.2 g, 0.25 mmol) was treated with 5 mL of 4N HCl in dioxane undernitrogen. The reaction mixture was stirred for 3 hours at roomtemperature, then the mixture was concentrated under reduced pressure.Methylene chloride (several mL) was added to the concentrated residueand then removed under reduced pressure. The resulting residue was driedin vacuo to give 0.21 g of the desired deprotected piperazine sulfone asa white solid. This solid was recrystalized from ethyl acetate and etherto produce 80 mg (44.4%) of pure product as a white solid: HRMS: calcdfor C₃₂ H₄₆ N₄ O₉ S₂ 695.2784, found 695.2812.

EXAMPLE 56 ##STR87## Preparation of N- 2R-hydroxy-3-(2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethy)propyl!-2S-methyl-3- (2-(4-oxomorpholin-4-yl)ethyl)aminocarbonyl!methyl!sulfonyl!propanamide

Part A: Preparation of N-(2-chloroacetyl)-2-(4-morpholinyl)ethylamine

Chloroacetyl chloride (1.73 g, 15 mmol) was dissolved in 4 mL ofdichloromethane and cooled to 5° C. in an ice-water bath.4-(2-Aminoethyl)morpholine (2 g, 15 mmol) was dissolved in 4 mL ofdichloromethane containing triethylamine (3.03 g, 30 mmol) which wasthen added to this cold solution at 5° C. A solid precipitate formedimmediately after the triethylamine was added. The reaction mixture wasstirred for 3 hours at room temperature. The reaction mixture wasdiluted with 100 mL of dichloromethane and 20 mL of water. The organicsolution was washed with 5% aqueous NaHCO₃ (2×50 mL), brine (1×50 mL),dried over MgSO₄, filtered and concentrated under reduced pressure. Theresulting residue was dried in vacuo to give 2.57 g (83.7%) ofN-(2-chloroacetyl)-2-(4-morpholinyl)ethylamine as a yellow solid. ¹ HNMR (300 MHz / CDCl₃): ∂ 2.48-2.55 (m, 6H), 3.38 (dd, 2H, J=5.63 Hz),3.71 (t, 4H, J=4.53 Hz), 4.04 (s, 2H); mass spectrum, m/z=207.1 (M+H);HRMS calcd for C₈ H₁₅ N₂ O₂ Cl₁ 206.0822, found 206.0814.

Part B: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (2-(4-oxomorpholin-4-yl)ethyl)aminocarbonyl!methyl!thio!propanamide

To an ice-cold solution of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide(0.5 g, 0.96 mmol) in 8 mL of dichloromethane was addedN-(2-chloroacetyl)-2-(4-morpholinyl)ethylamine (0.2 g, 0.96 mmol) in 8mL of dichloromethane containing triethylamine (0.14 g, 1.43 mmol). Thereaction mixture was stirred for 1 hour at 5° C. then warmed up to roomtemperature and stirred for 60 hours at room temperature. The reactionmixture was diluted with 150 mL of dichloromethane. The organic solutionwas washed with 5% aqueous NaHCO₃ (2×100 mL), water (2×100 mL), brine(2×100 mL), dried over MgSO₄, filtered and concentrated under vacuum.The resulting residue was purified by flash chromatography on silica geleluting with a 0-6% methanol gradient in dichloromethane to give 0.33 g(49.8%) of the desired sulfide product as a white solid: HRMS calcd forC₃₃ H₄₈ N₄ O₈ S₂ 693.2992, found 693.2997.

Part C: N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (2-(4-oxomorpholin-4-yl)ethyl)aminocarbonyl!methyl!sulfonyl!propanamide

To a solution of the sulfide product from Part B (0.25 g, 0.36 mmol) inmethanol (10 mL) was added oxone (0.66 g, 1.08 mmol) and water (2 mL).The reaction mixture was stirred for 24 hours at room temperature, andthen the methanol was removed at reduced pressure. The concentratedresidue was brought up in 150 mL of ethyl acetate. The organic solutionwas washed with saturated aqueous NaHCO₃ (2×100 mL), water (2×100 mL),brine (2×100 mL), dried over MgSO₄, filtered and concentrated at reducedpressure. The concentrated residue was dried in vacuo to give 0.15 g(56.1%) of the desired sulfone product as a yellow solid: HRMS: calcdfor C₃₃ H₄₈ N₄ O₁₁ S₂ 741.2839 (M+H), found 741.2803.

EXAMPLE 57 Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (4-morpoholinylcarbonyl)methyl!lsulfonyl!propanamide ##STR88## Part A: Preparation of4-(2-chloroacetyl)morpholine

To an ice cold solution of chloroacetyl chloride (1.29 g, 11 mmol) in 10mL of methylene chloride was added morpholine (1 g, 11 mmol) in 10 mL ofmethylene chloride containing triethylamine (2.32 g, 23 mmol). Thereaction mixture was stirred at 5° C. for 30 minutes then warmed to roomtemperature and stirred for 18 hours. After quenching with water (20 mL)at 5° C., additional methylene chloride (100 mL) was added. The organiclayer was separated, washed with 1N HCl (1×50 mL), saturated aqueousNaHCO₃ (1×50 mL), brine (1×50 mL), dried over MgSO₄, filtered andconcentrated at reduced pressure. The concentrated residue was dried invacuo to give 0.52 g (28.8%) of 4-(2-chloroacetyl)morpholine as a brownoil. ¹ H NMR (300 MHz / CDCl₃): δ 3.51-3.54 (m, 2H), 3.61-3.64 (m, 2H),3.68-3.74 (m, 4H), 4.06 (s, 2H). HRMS: calcd for C₆ H₁₀ N₁ O₂ Cl₁164.0478, found 164.0498.

Part B: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (4-morpholinylcarbonyl)methyl!thio!propanamide

To an ice-cold solution of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide(1.60 g, 3.07 mmol) in 10 mL of dichloromethane was added4-(2-chloroacetyl)morpholine (0.50 g, 3.07 mmol) in 5 mL ofdichloromethane containing triethylamine (0.31 g, 3.07 mmol). The icebath was removed, and the reaction mixture was stirred for 24 hours atroom temperature. The reaction mixture was then diluted with 200 mL ofdichloromethane. The organic solution was washed with 1N HCl (2×100 mL),saturated aqueous NaHCO₃ (2×100 mL), brine (2×100 mL), dried over MgSO₄,filtered and concentrated. The resulting residue was purified by flashcolumn chromatography on silica gel eluting with 80% ethyl acetate inhexane to give 1.61 g (80.8%) of the desired sulfide product as a paleyellow solid: HRMS calcd for C₃₁ H₄₃ N₃ O₈ S₂ 650.2570, found 650.2583.

Part C: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (4-morpholinylcarbonyl)methyl!sulfonyl!propanamide

To a solution of the sulfide compound from Part B (0.50 g, 0.77 mmol) inmethanol (13 mL) was added oxone (1.66 g, 2.7 mmol) and water (1.5 mL).The reaction mixture was stirred for 18 hours at room temperature, thencooled in an ice-water bath, and saturated aqueous NaHCO₃ (5 mL) wasadded. The methanol was removed at reduced pressure, and the residue wasbrought up in 150 mL of methylene chloride. The organic solution waswashed with 5% aqueous NaHCO₃ (2×100 mL), water (2×100 mL), brine (2×100mL), dried over MgSO₄, filtered and the filtrate was concentrated atreduced pressure. The concentrated residue was dried in vacuo to give0.47 g (89.5%) of the desired sulfone as a white solid: HRMS: calcd forC₃₁ H₄₃ N₃ O₁₀ S₂ 682.2468, found 682.2454.

EXAMPLE 58 ##STR89## Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- 4-(t-butoxycarbonyl)piperazin-1-ylcarbonyl!methyl!sulfonyl!propanamide

Part A: Preparation of1-(2-chloroacetyl)-4-(tert-butoxycarbonyl)piperazine

To an ice-cold solution of chloroacetyl chloride (1.27 g, 10 mmol) in 15mL of methylene chloride was added N-tert-butoxycarbonylpiperazine (1.27g, 11 mmol) in 10 mL of methylene chloride containing triethylamine(2.17 g, 20 mmol). The reaction mixture was stirred at 5° C. for 30minutes, then warmed to room temperature and stirred for 24 hours. Water(20 mL) was added at 5° C., and the reaction mixture was diluted withmethylene chloride (200 mL). The organic layer was separated, washedwith saturated aqueous NaHCO₃ (2×100 mL), brine (2×100 mL), dried overMgSO₄, filtered, and concentrated at reduced pressure. The concentratedresidue was purified by flash column chromatography on silica geleluting with ethyl acetate to give 2.20 g (84.0%) of1-(2-chloroacetyl)-4-(tert-butoxycarbonyl)piperazine as a yellow liquid.¹ H NMR (300 MHz / CDCl₃): δ 1.46 (s, 9H), 3.41-3.60 (m, 8H), 4.07 (s,2H). HRMS: calcd for C₁₁ H₁₉ N.sub. O₃ Cl₁ 262.1084, found 262.1079.

Part B: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- 4-(t-butoxycarbonyl)piperazin-1-ylcarbonyl!methyl!thio!propanamide

To an ice-cold solution of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide(0.60 g, 0.96 mmol) in 10 mL of dichloromethane was added1-(2-chloroacetyl)-4-(tert-butoxycarbonyl)piperazine (0.30 g, 0.96 mmol)in 5 mL of dichloromethane containing triethylamine (0.17 g, 1.43 mmol).The reaction mixture was stirred for 72 hours at room temperature. Thereaction mixture was then diluted with 150 mL of dichloromethane. Theorganic solution was washed with saturated aqueous NaHCO₃ (2×100 mL),brine (2×100 mL), dried over MgSO₄, filtered, and the filtrate wasconcentrated under vacuum. The resulting residue was purified by flashcolumn chromatography on silica gel eluting with 60% ethyl acetate inhexane to give 0.57 g (79.7%) of the desired sulfide as a white solid:HRMS calcd for C₃₆ H₅₂ N₄ O₉ S₂ 749.3254, found 749.3266.

Part C: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- 4-(t-butoxycarbonyl)piperazin-1-ylcarbonyl!methyl!sulfonyl!propanamide

To a solution of the sulfide product from Part B (0.30 g, 0.38 mmol) inmethanol (10 mL) was added oxone (0.83 g, 1.35 mmol) and water (1.5 mL).The reaction mixture was stirred for 20 hours at room temperature. Thereaction mixture was cooled in an ice-water bath, and water (10 mL) wasadded. The methanol was then removed at reduced pressure. Theconcentrated residue was brought up in 150 mL of methylene chloride. Theorganic solution was washed with saturated aqueous NaHCO₃ (2×100 mL),water (2×100 mL), brine (2×100 mL), dried over MgSO₄, filtered, and thefiltrate was concentrated at reduced pressure. The concentrated residuewas dried in vacuo to give 0.24 g (76.7%) of the desired sulfone productas a pale yellow solid: HRMS: calcd for C₃₆ H₅₂ N₄ O₁₁ S₂ 781.3152,found 781.3141.

EXAMPLE 59 ##STR90## Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(piperazin-1-ylcarbonyl)methyl!sulfonyl!propanamide.multidot.hydrochloride

N- 2R-Hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-4-(t-butoxycarbonyl)piperazin-1-ylcarbonyl!methyl! sulfonyl!propanamide(0.15 g, 0.19 mmol) was treated with 5 mL of 4 N HCl in dioxane undernitrogen. The reaction mixture was stirred for 3 hours at roomtemperature, then the mixture was concentrated under reduced pressure.Toluene (several mL) was added to the concentrated residue then removedunder reduced pressure. The resulting residue was dried in vacuo to give0.12 g (87.2%) of the desired product as a pale yellow solid: HRMS:calcd for C₃₁ H₄₄ N₄ O₉ S₂ 681.2628, found 681.2614.

EXAMPLE 60 Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(phenacy!sulfonyl)-propanamide ##STR91## Part A:Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(phenacylthio)propanamide

To an ice-cold solution of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide(0.1 g, 0.19 mmol) and DBU (0.032 g, 0.21 mmol) in 1 mL of anhydrous THFwas added phenacyl chloride (Aldrich, 0.04 g, 0.21 mmol) dissolved in 1mL of anhydrous THF. Then the ice bath was removed, and the reactionmixture was stirred for 20 minutes at room temperature. The THF wasremoved at reduced pressure, and the concentrated residue was dilutedwith 100 mL of ethyl acetate. The organic solution was washed withaqueous 3% KHSO₄ (2×50 mL), brine (2×50 mL), dried over MgSO₄, filtered,and the filtrate was concentrate under vacuum. The resulting residue wasdried in vacuo to give 0.12 g (98.2%) of the desired sulfide product asa solid: HRMS calcd for C₃₃ H₄₀ N₂ O₇ S₂ 641.2355, found 641.2340.

Part B. Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(phenacy1Sulfonyl)propanamide

To a solution of the sulfide product from Part A (0.05 g, 0.08 mmol) inmethanol (2 mL) was added oxone (0.17 g, 0.27 mmol) and water (0.2 mL).The reaction mixture was stirred for 18 hours at room temperature. Themethanol was removed at reduced pressure, and the residue was brought upin 30 mL of ethyl acetate. The organic solution was washed with 5%aqueous NaHCO₃ (1×20 mL), water (1×20 mL), brine (1×20 mL), dried overMgSO₄, filtered, and the filtrate was concentrated at reduced pressure.The concentrated residue was purified by flash column chromatography onsilica gel eluting with 50% ethyl acetate in hexane to give 0.06 g(28.5%) of the desired sulfone as a white solid: HRMS: calcd for C₃₃ H₄₀N₂ O₉ S₂ 673.2254, found 673.2259.

EXAMPLE 61 ##STR92## Preparation of N- b 2R-hydroxy-3- (2-methylpronyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1,1-dioxothiomorpholin-1-ylcarbonyl)methyl!sulfonyl!propanamide

Part A: Preparation of 4-(2-chloroacetyl)thiomorpholine

To an ice-cold solution of chloroacetyl chloride (2.87 g, 25 mmol) in 15mL of methylene chloride was added thiomorpholine (2.50 g, 24 mmol) andtriethylamine (4.9 g, 48 mmol) slowly. The reaction mixture was stirredat 5° C. for 30 minutes, then warmed to room temperature and stirred for18 hours. After quenching with water (20 mL) at 5° C., additionalmethylene chloride (200 mL) was added. The organic layer was separated,washed with saturated aqueous NaHCO₃ (2×100 mL), brine (2×100 mL), driedover MgSO₄, filtered, and the filtrate was concentrated at reducedpressure. The concentrated residue was dried in vacuo to give 1.83 g(42.0%) of 4-(2-chloroacetyl) thiomorpholine as a brown liquid. 1_(H)NMR (300 MHz / CDCl₃):.sup.δ 2.62 (t, 2H, J=5.03 Hz), 2.68 (t, 2H,J=4.93Hz), 3.75 (t, 2H, J=5.04 Hz), 3.85 (t, 2H, J=5.04 Hz), 4.04 (s,2H); mass spectrum, m/z =180.2 (M+H).

Part B: Preparation of N- b 2R-hydroxy-3- (2-methylpronyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1,1-dioxothiomorpholin-1-ylcarbonyl)methyl!thio!propanamide

To an ice-cold solution of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide(0.3 g, 0.57 mmol) in 5 mL of dichloromethane was added4-(2-chloroacetyl)thiomorpholine (0.10 g, 0.57 mmol) in 5 mL ofdichloromethane containing triethylamine (0.09 g, 0.86 mmol). After theaddition, the ice bath was removed, and the reaction mixture was stirredfor 18 hours at room temperature. The reaction mixture was then dilutedwith 150 mL of dichloromethane. The organic solution was washed with 1NHCl (1×100 mL), saturated aqueous NaHCO₃ (1×100 mL), brine (2×100 mL),dried over MgSO₄, and filtered. The filtrate was concentrated and driedin vacuo. The resulting residue was purified by flash columnchromatography on silica gel eluting with a 40-60% gradient of ethylacetate in hexane to give 0.4 g (99%) of the desired sulfide product asa pale yellow solid: HRMS calcd for C₃₁ H₄₃ N₃ O₇ S₃ 666.2341, found666.2370.

Part C: Preparation of N- b 2R-hydroxy-3- (2-methylpronyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1,1-dioxothiomorpholin-1-ylcarbonyl)methyl!sulfonyl!propanamide

To a solution of the sulfide compound from Part B (0.28 g, 0.42 mmol) inmethanol (10 mL) was added oxone (1.55 g, 2.52 mmol) and water (2 mL).The reaction mixture was stirred for 18 hours at room temperature, andthe methanol was removed at reduced pressure. The concentrated residuewas brought up in 150 mL of ethyl acetate. The organic solution waswashed with saturated aqueous NaHCO₃ (2×100 mL), water (2×100 mL), brine(2×100 mL), dried over MgSO₄, filtered, and the filtrate wasconcentrated at reduced pressure. The concentrated residue was dried invacuo to give 0.04 g (13.0 %) of the desired product as a white solid:HRMS: calcd for C₃₁ H₄₃ N₃ O₁₁ S₃ 730.2138, found 730.2151.

EXAMPLE 62 ##STR93## Preparation of N- b 2R-hydroxy-3- (2-methylpronyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (3-(ethoxycarbonyl)propylthiol propanamide

Part A: Preparation of ethyl 4-bromobutyrate

To a solution of 4-bromobutyric acid (3 g, 18 mmol) in ethanol (30 mL)was added 5 mL of 4N HCl in dioxane. The reaction mixture was stirredfor 16 hours at room temperature, and then the volatile components wereremoved under vacuum. The concentrated residue was brought up in 150 mLof methylene chloride. The organic solution was washed with saturatedaqueous NaHCO3 (1 x 150 mL), brine (1×150 mL), dried over MgSO₄,filtered, and the filtrate was concentrated at reduced pressure. Theconcentrated residue was dried in vacuo to give 3 g (85.5%) of the knownproduct as a yellow oil. ¹ H NMR (300 MHz/CDCl₃): .sup.δ 1.22 (t, 3H,J=7.15 Hz), 2.13 (overlapping t, 2H, J=6.80 Hz), 2.45 (t, 2H, J=7.15Hz), 3.43 (t, 2H, J=6.44 Hz), 4.10 (q, 2H, J=7.25 Hz).

Part B: Preparation of N- b 2R-hydroxy-3- (2-methylpronyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (3-(ethoxycarbonyl)propylthiol propanamide

To an ice-cold solution of ethyl 4-bromobutyrate (0.11 g, 0.574 mmol)and DBU (0.087 g, 0.574 mol) in 5 mL of THF was added N- 2R-hydroxy-3-(2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide (0.3 g, 0.574 mmol) in 5 mL ofTHF. The cold reaction mixture was warmed to room temperature andstirred 2 hours. Then the THF was removed under vacuum, and the residuewas brought in 150 mL of methylene chloride. The organic solution waswashed with 1N HCl (1×100 mL), saturated aqueous NaHCO₃ (1×100 mL),brine (1×100 mL), dried over MgSO₄, filtered, and the filtrate wasconcentrated. The crude residue was purified by flash columnchromatography on silica gel eluting with diethyl ether to give 0.16 g(43.8%) of the desired product as a white gummy solid: HRMS: calcd forC₃₁ H₄₄ N₂ O₈ S₂ 637.2617, found 637.2632.

EXAMPLE 63 Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1H-imidazol-4-ylmethyl)sulfonyl! ##STR94## Part A:Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1H-imidazol-4-ylmethyl)thio! propanamide

To a solution of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide (0.25 g, 0.48 mmol) in dry DMF(2.0 mL), DBU (0.163 g, 1.07 mmol) was added, and the reaction mixtruewas stirred under argon. After 15 minutes, 4-chloromethylimidazolehydrochloride (0.08 g, 0.52 mmol) (prepared according to Tsung-YingShen, U.S. Pat. No. 3,438,992) was added, and the mixture was stirred atroom temperature for 4 hours. The DMF was removed in vacuo, and theresidue was partitioned between ethyl acetate (25 mL) and water (10 mL).The organic layer was washed successively with saturated aqueous NaHCO₃(2×10 mL), water (3×10 mL) and dried (Na₂ SO₄). After removal of thesolvent, the residue was washed with ether and filtered to give thedesired sulfide as a white powder (0.19 g), FAB-MS m/z=603 (M+H).

Part B: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1H-imidazol-4-ylmethyl)sulfonyl! propanamide

The sulphide obtained in Part A, was dissolved in a mixture of methanol(4.0 mL) and water (1.0 mL), oxone (0.18 g, 0.29 mmol) was added, andthe reaction mixture stirred at room temperature for 1 hour. Water (10mL) was then added, and the reaction was cooled, neutralized withaqueous NaHCO₃ (5%) and extracted with ethyl acetate (2×15 mL). Thecombined orgranic extracts were washed with water (3×15 mL), dried (Na₂SO₄) and concentrated under reduced pressure. The resulting substancewas purified by reverse-phase HPLC using 10-90% CH₃ CN--H₂ O (30 minutegradient) at a 70 mL/min flow rate to give the desired imidazole sulfoneas a white powder (0.078 g, 22%): Rt 14.8 min (10-90% CH₃ CN--H₂ O at 1mL/min); high-resolution FAB-MS calcd for C₂₉ H₃₉ N₄ O₈ S₂ 635.2209,found 635.2196.

EXAMPLE 64 ##STR95## Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1.3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1H-pyrazol-3-ylmethyl)sulfonyl!propanamide

Part A: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1H-pyrazol-3-ylmethyl)thio! propanamide

A mixture of 3-chloromethylpyrazole hydrochloride (0.1 g, 0.65 mmol)(prepared according to Tsung-Ying Shen, U.S. Pat. No. 3,438,992),potassium bromide (0.1 g, 0.84 mmol) and 18-crown-6 (0.025 g) in dry DMF(1 mL) was heated at 70° C. for 2 hours under a nitrogen atmosphere. Thereaction mixture was cooled, then a solution of N- 2R-hydroxy-3-(2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide(0.25 g, 0.48 mmol) in DMF (2 mL) containing DBU (0.2 g, 1.3 mmol) wasadded and stirred at room temperature for 4 hours. The DMF was distilledaway in vacuo, and the residue was partitioned between ethyl acetate (20mL) and water (10 mL). The organic phase was washed with brine (2×15mL), dried (Na₂ SO₄), and concentrated under reduced pressure. Theresulting material was purified by flash column chromatography on silicagel eluting with ethyl acetate to give the desired pyrazole sulfide as awhite amorphous substance (0.075 g, 26%). FAB-MS m/z 603 (M+H);high-resolution FAB-MS calcd for C₂₉ H₃₉ N₄ O₆ S₂ 603.2311, found603.2321.

Part B: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1H-pyrazol-3-ylmethyl)sulfonyl! propanamide

The sulphide product obtained in Part A, was dissolved in MeOH (2.0 mL)containing water (0.5 mL). Oxone (0.18 g, 0.3 mmol) was added, and thereaction mixture stirred at 0° C. for 30 minutes then at roomtemperature for 30 minutes. The reaction mixture was concentrated underreduced pressure. The resulting residue was partitioned betweensaturated aqueous sodium bicarbonate (25 mL) and EtOAc (40 mL). Theorganic phase was washed with brine, dried (Na₂ SO₄), and concentrated.The resulting material was purified by reverse-phase HPLC using a 5-70%CH₃ CN/H₂ O gradient (30 min) at a 70 mL/min flow rate. The appropriatefractions were pooled and freeze-dried to give the desired sulfoneproduct (0.05 g, 57%) as a white powder: Rt=16.7 min; high-resolutionFAB-MS calcd for C₂₉ H₃₉ N₄ O₈ S₂ 635.2209, found 635.2201.

EXAMPLE 65 ##STR96## Preparation of N- 2R-hvdroxy-3- (2-methylproply)(1,3-benzodioxol-5-yl)sulfonyl!amino!1S-(phenylmethyl)propyl!-2S-methyl-3- (1H-pyrazol-4-ylmethyl)sulfonyl!propanamide

Part A: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1H-pyrazol-4-ylmethyl)thio! propanamide

A mixture of 4-chloromethylpyrazole hydrochloride (0.17 g, 1.1 mmol)(prepared according to Tsung-Ying Shen, U.S. Pat. No. 3,438,992), KBr(0.28 g, 2.4 mmol) and 18-crown-6 (0.03 g, 0.11 mmol) indimethylacetamide (2 mL) was stirred at ambient temperature for 4 hours,and then a solution of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide (0.38 g, 0.73 mmol) indimethylacetamide containing DBU (0.235 g, 1.5 mmol) was added. Thereactants were stirred overnight at ambient temperature, thedimethylacetamide was distilled in vacuo, and the residue waspartitioned between 5% aqueous citric acid (10 mL) and ethyl acetate (25mL). The ethyl acetate extract was washed with water (3×15 mL), dried(Na₂ SO₄) and concentrated under reduced pressure. The resultingsubstance was purified by flash column chromatography on silica geleluting with ethyl acetate to give the desired sulfide as an amorphouswhite substance (0.2 g), FAB-MS m/z=603 (M+H), high-resolution FAB-MScalcd for C₂₉ H₃₉ N₄₀₆ S₂ 603.2311, found 603.2317.

Part B: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1H-pyrazol-4-ylmethyl)sulfonyl! propanamide

The sulfide as prepared in Part A, was dissolved in MeOH (6.0 mL), water(2.0 mL), and oxone (0.5 g, 0.8 mmol) was added. After stirring for 30minutes at ambient temperature, the reaction mixture was filtered, andthe filtrate was concentrated. The resulting residue was partitionedbetween saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate(40 mL). The organic phase was washed with brine, dried (Na₂ SO₄) andconcentrated. The resulting solid was purified by reverse-phase HPLCusing a 10-90% CH₃ CN/H₂ O gradient (30 min) at a flow rate of 70 mL/minto give the desired sulfone as a white powder: R_(t) =17.4 min;high-resolution FAB-MS calcd for C₂₉ H₂₉ N₄ O₈ S₂ 635.2209, found635.2209.

EXAMPLE 66 Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1H-benzimidazol-2-ylmethyl) sulfonyl!propanamide##STR97## Part A: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1H-benzimidazol-2-ylmethyl)thio! propanamide

A mixture of 2-(chloromethyl)benzimidazole (0.24 g, 1.44 mmol), KBr (0.3g, 2.5 mmol) and 18-crown-6 (0.05 g, 0.19 mmol) in dimethylacetamide(2.5 mL) was stirred at room temperature for 2 hours, and then asolution of N- 2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide(0.5 g, 1 mmol) in dimethylacetamide (2.5 mL) containing DBU (0.26 g,1.7 mmol) was added. After stirring the reaction mixture at roomtemperature for 2 hours, it was concentrated in vacuo, and the residuewas partitioned between 5% aqueous citric acid (20 mL) and ethyl acetate(25 mL). The ethyl acetate extract was washed successively with 5%citric acid (2 ×10 mL), water (3×15 mL), dried (Na₂ SO₄) andconcentrated to dryness. The residue was purified by flash columnchromatography on silica gel eluting with ethyl acetate to give thedesired sulfide as a pale yellow amorphous substance: R_(t) =18.8 min;FAB-MS: m/z=653 (M+H), high-resolution FAB-MS: calcd for C₃₃ H₄₁ N₄₀₆ S₂653.2468, found 653.2459.

Part B. Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1H-benzimidazol-2-ylmethyl) sulfonyl!propanamide

To a solution of the sulfide (0.22 g, 0.34 mmol) as obtained in Part A,in MeOH (6.0 mL) and water (2.00 mL), oxone (0.5 g, 0.8 mmol) was added.The reaction mixture was stirred at 10° C. for 1 hour and filtered. Thefiltrate was concentrated under reduced pressure, and the residue waspartitioned between ethyl acetate (35 mL) and saturated aqueous sodiumbicarbonate (20 mL). The ethyl acetate extract was washed with water(2×15 mL), dried (Na₂ SO₄), and concentrated to dryness. The resultingsubstance was purified by flash column chromatography on silica geleluting with ethyl acetate. The appropriate fractions were combined andevaporated to give a white amorphous solid. This substance was washedwith 5% ethyl acetate in ether and dried in vacuo to afford the desiredsulfone as a white powder (0.15 g, 65%): Rt=18.1 min; high-resolutionFAB-MS calcd for C₃₃ H₄₁ N₄ O₈ S₂ 685.2366, found 685.2376.

EXAMPLE 67 ##STR98##

Preparation of N- 2R-hvdroxy-3-(2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyllaminol -1S-(Dhenylmethyl) proyl!-2S-methyl-3-(thiazol-5-ylmethyl) sulfonyl!propanamide

Part A: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (thiazol-5-ylmethyl)thio!propanamide

A mixture of 5-chloromethylthiazole hydrochloride (0.22 g, 1.29 mmol)(prepared according to Bruneau, P. A. R. et. al. EP 284174; CA110:192811), KBr (0.34 g, 2.85 mmol), 18-crown-6 (0.05 g, 0.19 mmol) indimethyl acetamide (2.5 mL) was stirred at room temperature for 2 hours.Then a solution of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide (0.52 g, 1 mmol) and DBU (0.36g, 2.37 mmol) in dimethylacetamide (2.5 mL) was added. The resultingmixture was stirred at room temperature for another 2 hours and was thenconcentrated in vacuo. The resulting residue was partitioned betweenethyl acetate (30 mL) and 5% aqueous citric acid (10 mL). The organicphase was washed with water (3×10 mL), dried (Na₂ SO₄), concentrated todryness and the residue was purified by flash column chromatography onsilica gel eluting with 50% ethyl acetate in hexane to give the desiredthiazole sulfide as a pale yellow amorphous substance (0.43 g, 72%):Rt=18.6 min; high-resolution FAB-MS calcd for C₂₉ H₃₈ N₃ O₆ S₃620.1923,found 620.1913.

Part B: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (thiazol-5-ylmethyl)sulfonyl!propanamide

A mixture of the sulfide (0.15 g, 0.24 mmol) as prepared in Part A,oxone (0.33 g, 0.54 mmol) in MeOH (4.00 mL) and water (1.00 mL) wasstirred at 10° C. for 45 minutes and filtered. The filtrate wasconcentrated, and the residue was partitioned between ethyl acetate (40mL) and aqueous saturated sodium bicarbonate (20 mL). The organic phasewas washed with water, dried (Na₂ SO₄) and concentrated to dryness. Theresulting solid was purified by flash column chromatography on silicagel eluting with ethyl acetate. Fractions containing the major productwere combined, concentrated and dried under vacuum to give the desiredsulfone product as an amorphous substance (0.12 g, 76%): Rt=16.5 min;high-resolution FAB-MS calcd for C₂₉ H₃₈ N₃ O₈ S₃ 652.1821,found652.1822.

EXAMPLE 68 ##STR99## Preparation of N- 2R-hvdroxy-3- (2-methylproTyl)(1,3-benzodioxol-5-vl)sulfonyl!aminol!1S-(-phenylmethyl)proloyl!-2S-methyl-3- (1H-pyrrolidin-2S-vlmethyl) sulfonyl!porotanamide

Part A: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-1-(benzyloxycarbonyl)pyrrolidin-2S-ylmethyl!thio!propanamide

To a solution of L-N-Cbz-2-bromomethylpyrrolidine (0.32 g, 1.07 mmol)(prepared according to J. Org. Chem. 48 (22), 4058-67, 1983) and DBU(0.2 g, 1.3 mmol) in dimethyl acetamide (3 mL), was added a solution ofN- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide (0.5 g, 0.96 mmol) in dimethyl acetamide (2 mL), and thereaction mixture was stirred at room temperature for 2 hours under anargon atmosphere. The dimethylacetamide was distilled in vacuo, and theresidue was partitioned between ethyl acetate (25 mL) and 5% aqueouscitric acid (15 mL). The organic phase was washed with water (2×15 mL),dried (Na₂ SO₄), and concentrated. The resulting substance was purifiedby flash column chromatography on silica gel eluting with ethyl acetatein hexane (1:1 , v/v) to give the desired pyrrolidine-substitutedsulfide (0.4 g, 57%) as a white amorphous material: FAB-MS m/z 746(M+Li); high-resolution FAB-MS calcd for C₃₈ H₅₀ N₃ O₈ S₂ 740.3039(M+H), found 740.3022.

Part B: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl) sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-1-(benzyloxycarbonyl)pyrrolidin-2S-ylmethyl!sulfonyl!propanamide

A mixture of the sulfide prepared as described in Part A (0.33 g, 0.45mmol), and oxone (0.69 g, 1.1 mmol) in methanol (8.00 mL) and water(2.00 mL) was stirred at 10° C. for 30 minutes. After stirring at roomtemperature for 1.5 hours, the mixture was filtered, and the filtratewas concentrated. The resulting residue was partitioned betweensaturated aqueous sodium bicarbonate (15 mL) and ethyl acetate (35 ML).The organic phase was washed with water (2×25 mL), dried (Na₂ SO₄), andconcentrated. The resulting residue was purified by flash columnchromatography on silica gel eluting with 60% ethyl acetate in hexane togive the desired N-carbobenzyloxy-pyrrolidine-substituted sulfone (0.25g, 74%) as an amorphous white solid: Rt=24.7 min; high-resolution FAB-MScalcd for C₃₈ H₅₀ N₃ O₁₀ S₂ 772.2938,found 772.2931.

Part C: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1H-pyrrolidin-2S-ylmethyl) sulfonyl!propanamide

A solution of the sulfone product from Part B (0.12 g, 0.16 mmol) inmethanol (10 mL) was hydrogenated at 50 psi in the presence of 10% Pd/C(0.15 g) at room temperature for 4 hours. The catalyst was removed byfiltration, and the filtrate was evaporated to dryness under reducedpressure. The resulting residue was purified by reverse-phase HPLC usinga 10-90% CH₃ CN/H₂ O gradient (30 min) at a flow rate of 70 mL/min togive the desired deprotected pyrrolidine-substituted sulfone (0.07 g,60%) as a white powder: Rt=17.2 min; high-resolution FAB-MS calcd forC₃₀ H₄₄ N₃ O₈ S₂ 638.2570,found 638.2573.

EXAMPLE 69 ##STR100## Preparation of N- 2R-hydroxy-3- (2-methyloropyl)(1,3-benzodioxol-5-yl) sulfonyl!aminol!-1S-(phenylmethyl)proyl!-2S-methyl-3- (1H-pyrrolidin-2R-ylmethyl) sulfonyl!propanamide

Part A: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl) propyl!-2S-methyl-3-1-(benzyloxycarbonyl)pyrrolidin-2R-ylmethyl!thio!propanamid

Following the procedure described in Example 68,Part A, N- 2R-hydroxy-3-(2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- 1-(benzyloxycarbonyl)pyrrolidin-2R-ylmethyl!thio!propanamide was preparedfrom (D)-N-Cbz-2-bromomethyl-pyrrolidine (prepared according to Agric.Biol. Chem. 55 (1),37-43, 1991) in 70% yield: Rt=27.2 min;high-resolution FAB-MS calcd for C₃₈ H₅₀ N₃ O₈ S₂ 740.3039,found740.3038.

Part B: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-1-(benzyloxycarbonyl)pyrrolidin-2R-ylmethyl!sulfonyl!propanamide

Following the procedure described in Example 68, Part B, N-2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- 1-(benzyloxycarbonyl)pyrrolidin-2R-ylmethyl!sulfonyl!propanamide wasprepared from the (D)-N-cbz-2-pyrrolidine sulfide of Part A above in 72%yield: Rt=24.9 min; FAB-MS m/z=778 (M +Li); high-resolution FAB-MS calcdfor C₃₈ H₅₀ N₃ O₁₀ S₂ 772.2938 (M+H), found 772.2940.

Part C: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1H-pyrrolidin-2R-ylmethyl)sulfonyl!propanamide

Following the procedure described in Example 68, Part C, N-2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3 -(1H-pyrrolidin-2R-ylmethyl)sulfonyl!propanamide was prepared from the(D)-N-cbz-2-pyrrolidine sulfone of Part B above in 85% yield: Rt=17.4min; high-resolution FAB-MS calcd for C₃₀ H₄₄ N₃ O₈ S₂ (M+H)638.2570,found 638.2584.

EXAMPLE 70 ##STR101## Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1.3 -benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyridinylsulfonvl)propanamide

Part A: Preparation of methyl 3-(2-pyridylthio)-2S-methylpropionate

To a solution of 2-mercaptopyridine (1.4 g, 12.6 mmol) in dry THF (10mL), DBU (1.94 g, 12.75 mL) was added, and the reaction mixture wasstirred at 0° C. After 15 minutes, a solution of methy3-bromo-2S-methylpropionate (2.0 g, 11.05 mmol) in THF (10 mL) was addeddropwise, and the mixture was stirred at 0° C. for 3 hours under anargon atmosphere. The solution was then concentrated under reducedpressure. The resulting residue was dissolved in ethyl acetate (50 mL),washed with saline (2×20 mL), dried (Na₂ SO₄) and concentrated. Theresulting material was purified by flash column chromatography on silicagel eluting with 20% ethyl acetate in hexane to give methyl3-(2-pyridylthio)-2S-methylpropionate (0.75 g, 32%) as a colorlessliquid: ¹ H-NMR (CD30D) d: 8.41 (m, 1H), 7.6 (m, 1H), 7.23 (d, 1H, J=8.1Hz), 7.06 (m, 1H), 3.65 (s, 3H), 3.35 (m, 2H), 2.86 (sextet, 1H), 1.25(d, 3H, J=7.2 Hz); FAB-MS m/z 218 (M+Li), 212 (M+H); high-resolutionFAB-MS calcd for C₁₀ H₁₄ NO₂ S 212.0745 (M+H), found 212.0731.

Part B: Preparation of 3-(2-pyridylthio)-2S-methylpropionic acid

A mixture of methyl 3-(2-pyridylthio)-2S-methylpropionate (0.6 g, 2.8mmol) and LiOH (0.21 g, 5 mmol) in methanol (4 mL) and water (1 mL) wasstirred at room temperature for 2.5 hours. After the removal of thesolvents under reduced pressure, water (20 mL) was added. Then themixture was cooled, acidified with 5% aqueous citric acid and theproduct was extracted with ethyl acetate (2×25 mL). The combined organicextracts were washed with saline (2×20 mL), dried (Na2SO4) andconcentrated under reduced pressure to afford the acid (0.48 g, 86%) asa pale yellow powder: ¹ H-NMR (CD₃ OD) d: 8.36 (m, 1H), 7.58 (m, 1H),7.26 (d, 1H, J=8.1 Hz), 7.06 (m, 1H), 3.36 (m, 2H), 2.78 (sextet, 1H),1.26 (d, 3H, J=7.2 Hz); FAB-MS m/z 198 (M+H); high-resolution FAB-MScalcd for C₉ H₁₂ O₂ NS 198.0589,found 198.0573.

Part C: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyridinylthio)propanamide

To a solution of 3-(2-pyridylthio)-2S-methylpropionic acid (0.5 g, 2.54mmol) and HOBt (0.6 g, 4 mmol) in dimethylformamide (5 mL) was added EDC(0.5 g, 3.1 mmol) and the reaction mixture was stirred at 0° C. for 1hour. Then a solution of l- N-(l,3-berfzodioxol-5-yl)sulfonyl!-N-(2-methylpropyl)amino!-3(S)-amino-4-phenyl-2(R)-butanol(0.97 g, 2.3 mmol) in CH₂ C₁₂ (5 mL) was added, and the mixture wasstirred at room temperature for 4 hours. The solvents were distilled invacuo, and the residue was partitioned between saturated aqueous sodiumbicarbonate (25 mL) and ethyl acetate (45 mL). The organic phase waswashed successively with saturated aqueous sodium bicarbonate (2×20 mL),water, dried (Na₂ SO₄), and concentrated. The resulting residue waspurified by flash column chromatography on silica gel eluting with ethylacetate in hexane (1:1, v/v) to give the desired sulfide (1.2 g, 87%) asan amorphous 1:4 diasteromeric mixture: high-resolution FAB-MS calcd forC₃₀ H₃₈ N₃ O₆ S₂ 600.2202,found 600.2200.

Part D: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyridinylsulfonyl)propanamide

To a solution of the sulfide (0.5 g, 0.83 mmol) of Part C in methanol (8mL) and water (2.0 mL), oxone (1.3 g, 2.1 mmol) was added, and thereaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was filtered, and the filtrate was treated with coldsaturated aqueous sodium bicarbonate (50 mL), then extracted with ethylacetate (2×25 mL). The combined organic extracts were washed with water(2×20 mL), dried (Na₂ SO₄), and concentrated. The resulting residue waspurified by flash column chromatography on silica gel eluting with 80%ethyl acetate in hexane to give the desired sulfone (0.38 g, 72%) as awhite amorphous product: Rt=20.4 min; high-resolution FAB-MS calcd forC₃₀ H₃₈ N₃ O₈ S₂ 632.2100,found 632.2127.

EXAMPLE 71 ##STR102## Preparation of N- 2R-hydroxv-3- (2-methylproovl)(1,3 -benzodioxol-5-yl)sulfonyl!amino!-1S-(Dhenvlmethvl)propyl!-2S-methyl-3- (1,3-dihvdroxvpron-2-yl)methyl!sulfonyl!proropanamide

Part A. Preparation of 1,3-O-benzylidene-2 -(hydroxymethyl)propane

To a solution of 2-(hydroxymethyl)-1,3-propanediol (0.5 g, 4.7 mmol) andbenzaldehyde (1.04 g, 9.8 mmol) in CH₂ Cl₂ (5.00 mL), p-toluenesulfonicacid (0.1 g) was added, and the reaction mixture was stirred at roomtemperature for 3 hours. The reaction mixture was filtered, and CH₂ C₁₂(20 mL) was added to the filtrate. The filtrate was washed withsaturated aqueous sodium bicarbonate (2×20 mL), water (2×20 mL), dried(Na₂ SO₄) and concentrated to dryness. The resulting residue waspurified by flash column chromatography on silica gel eluting with 30%ethyl acetate in hexane to give the desired1,3-O-benzylidene-2-(hydroxymethyl) propane as a white solid: ¹ H-NMR(CD₃ OD) d: 7.5-7.3 (m, 5H), 5.54 & 5.46 (s, 1H), 4.3-4.1 (m, 3H), 3.94(d, 1H, J=7.8 Hz), 3.75 (t, 1H), 3.43 (d, 1H, J=6.0 Hz), 2.3 & 1.6 (m,1H); FAB-MS m/z=201 (M+Li); high-resolution FAB-MS calcd for C11H₁₅ O₃195.1021 (M+H), found 195.1027.

Part B. Preparation of 1,3-O-benzylidene-2 -(iodomethyl)propane

To a cold solution (0° C.) of 1,3-O-benzylidene-2-(hydroxymethyl)propane (0.45 g, 2.32 mmol) in acetonitrile (4 mL), asolution of methyltriphenoxy-phosphonium iodide (1.2 g, 2.65 mmol) wasadded, and the reaction mixture was stirred at 0° C. After 30 minutes,the reaction mixture was stirred at room temperature for 3 hours andthen concentrated under reduced pressure. The residue was dissolved inethyl acetate and washed successively with cold 0.25N NaOH (2×20 mL),water (3-20 mL), dried (Na₂ SO₄) and concentrated to dryness. Theresulting material was purified by flash column chromatography on silicagel eluting with ethyl acetate in hexane (1:1, v/v) to give the desirediodo derivative as a pale yellow liquid: ¹ H-NMR (CD₃ OD) d: 7.43-7.3(m, 5H), 5.52 & 5.43 (s, 1H), 4.35-4.2 (m, 3H), 3.65 (m, 2H), 3.01 (d,1H, J=6.9 Hz), 2.2 & 1.85 (m, 1H); FAB-MS m/z=305 (M+H); high-resolutionFAB-MS calcd for C₁₁ H₁₄ IO₂ 305.0038 (M+H), found 305.0043.

Part C. Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1,3-O-benzylideneprop-2-yl)methyl!thio!propanamide

To a solution of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide (0.64 g, 1.2 mmol), indimethylacetamide (5.0 mL), DBU (0.2 g, 1.3 mmol) was added, followed bythe addition of the iodo derivative (0.45 g, 1.48 mmol) from Part B. Thereaction mixture was stirred at room temperature for 3 hours andconcentrated in vacuo. The resulting residue was partitioned betweenethyl acetate (40 mL) and 5% aqueous citric acid (20 mL). The organicphase was separated, washed with water (2×20 mL), dried (Na₂ SO₄), andconcentrated. The resulting residue was purified by flash columnchromatography on silica gel eluting with ethyl acetate in hexane (1:1,v/v) to furnish the desired sulfide (0.53 g, 62%) as a white amorphoussolid: high-resolution FAB-MS calcd for C₃₆ H₄₇ N₂ O₈ S₂ 699.2744, found699.2800.

Part D. Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(1.3-O-benzylideneprop-2-yl)methyl!sulfonyl!propanamide

A mixture of the sulfide (0.5 g, 0.72 mmol) from Part C and oxone (1.1g, 1.78 mmol) in methanol (8.00 mL) and water (2.00 mL) was stirred at10° C. for 1 hour, and filtered. The fitrate was concentrated, 10%aqueous sodium bicarbonate (25 mL) was added, and the mixture wasextracted with EtOAc (2×25 mL). The combined organic extracts werewashed with brine, dried (Na₂ SO₄), and concentrated. The resultingresidue was purified by flash column chromatography on silica geleluting with ethyl acetate to give the desired sulfone (0.25 g, 48%) asa white powder: Rt=20.7 min; high-resolution FAB-MS calcd for C₃₆ H₄₇ N₂O₁₀ S₂ 731.2672, found 731.2687.

Part E. Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3- (1,3-dihydroxyprop-2-yl)methyl!sulfonyl!propanamide

A solution of the sulfone (0.2 g, 0.27 mmol) from Part D in ethanol (5.0mL) containing p-toluensulfonic acid (0.06 g, 0.3 mmol) was heated toreflux under a nitrogen atmosphere. After 1.5 hours, the solution wasconcentrated, and the residue was partitioned between ethyl acetate (25mL) and saturated aqueous sodium bicarbonate (10 mL). The organic phasewas washed with water, dried (Na₂ SO₄), and concentrated to dryness. Theresulting material was purified by reverse-phase HPLC using 10-90% CH₃CN/H₂ O (30 min gradient) as the mobile phase flowing at a rate of 70mL/min. The appropriate fractions were combined and freeze-dried to givea white powder. This material was dissoved in 0.25N NaOH (2 mL) andmethanol (3 mL), then stirred at room temperature for 45 minutes andconcentrated. The residue was partitioned between ethyl acetate (15 mL)and water (15 mL). The organic phase was washed with brine, dried (Na₂SO₄), concentrated and the residue was dried in vacuo to afford thedesired product (0.06 g, 34%) as a white powder: Rt=17.85 min;high-resolution FAB-MS calcd for C₂₉ H₄₃ N₂ O₁₀ S₂ 643.2359, found643.2386.

EXAMPLE 72 Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-vl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(l-methyl-5-deoxv-D-ribofuranosyl-5-yl)sulfonyl!propanamide ##STR103##Part A: Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(1-methyl-2.3-O-isopropylidene-5-deoxy-D-ribofuranosyl-5-yl)thio!propanamide

To a solution of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide(1.00 g, 1.9 mmol) in dimethylacetamide, (3.00 mL), DBU (0.35 g, 2.3mmol) and methyl-2,3-O-iso-propylidene-5-O-(p-tolyl sulfonyl)-D-riboside(0.75 g, 2.1 mmol) were added, and the reaction mixture was stirred atroom temperature for 2 hours. The DMA was distilled in vacuo, and theresidue was partitioned between 5% aqueous citric acid (30 mL) and ethylacetate (60 mL). The organic phase was washed with water (2×25 mL),dried (Na₂ SO₄), and concentrated. The resulting residue was purified byflash chromatography on silica gel eluting with 35% ethyl acetate inhexane (v/v) to give the desired sulfide (0.9 g, 66%) as a whiteamorphous solid: Rt=24.4 min; high-resolution FAB-MS calcd for C₃₄ H₄₉N₂ O₁₀ S₂ 709.2829, found 709.2813.

Part B. Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(l-methyl-2.3-O-isopropylidene-5-deoxy-D-ribofuranosyl-5-yl)sulfonyl!propanamide

A mixture of the sulfide (0.45 g, 0.64 mmol) from Part A, and oxone (0.9g, 1.46 mmol), in methanol (8.00 mL) and water (2.00 mL) was stirred at10° C. for 1.5 hours, and filtered. The filtrate was concentrated underreduced pressure, and the residue was partitioned between ethyl acetate(25 mL) and saturated aqueous sodium bicarbonate (25 mL). The organicphase was separated, washed with water (2×25 mL), dried (Na₂ SO₄), andconcentrated. The resulting residue was purified by flash chromatographyon silica gel eluting with ethyl acetate in hexane (1:1, v/v) to givethe desired sulfone (0.3 g, 64%) as a white amorphous powder: Rt=23.3min; high-resolution FAB-MS calcd for C₃₄ H₄₉ N₂ O₁₂ S₂ 741.2727, found741.2723.

Part C. Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(l-methyl-5-deoxy-D-ribofuranosyl-5-yl)sulfonyl!propanamide

To a solution of the sulfone (0.2 g, 0.27 mmol) from Part B in methanol(4.00 mL) and water (1.00 mL), p-toluenesulfonic (0.025 g, 0.13 mmol)was added, and the reaction mixture was heated to reflux under anitrogen atmosphere for 4 hours. The solution was concentrated underreduced pressure, and the residue was partitioned between ethyl acetate(20 mL) and saturated aqueous sodium bicarbonate (10 mL). The organicphase was separated, washed with water (2×10 mL), dried (Na₂ SO₄), andconcentrated. The resulting residue was purified by flash columnchromatography on silica gel eluting with ethyl acetate to give thedesired product (0.12 g, 63%) as an amorphous powder: Rt=16.6 min;high-resolution FAB-MS calcd for C₃₁ H₄₅ N₂ O₁₂ S₂ 701.2414, found701.2410.

EXAMPLE 73 Preparation of N- 2R-hydroxy-3- (2-methylproyl)(1.3-benzodioxol-5-yl)sulfonvl!amino!-1S-(phenylmethyl)propyl!-2S-methvl-3-(2-hydroxymethyl-1,3-dihvdroxyprop-2-yl)methyl!sulfonyl!propanamide##STR104## Part A. Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyllamino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-hydroxymethyl-1,3-dihydroxyprop-2-yl)methyl!thio!propanamide

To a solution of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-mercaptopropanamide (0.4 g, 0.77 mmol) indimethylacetamide (3.00 mL), DBU (0.204 g, 1.3 mmol) and2-(bromomethyl)-2-(hydroxymethyl)-1,3-propanediol (0.19 g, 0.95 mmol)were added. The resulting reaction mixture was stirred at roomtemperature for 1.5 hours and at 70° C. for 30 minutes. The DMA wasdistilled away in vacuo, and the residue was partitioned between 5%aqueous citric acid (10 mL) and ethyl acetate (25 mL). The organic phasewas washed with water (2×25 mL), dried (Na₂ SO₄), and concentrated. Theresulting residue was purified by flash column chromatography on silicagel eluting with 4% methanol in ethyl acetate to give the desiredsulfide (0.22 g, 45%) as a white amorphous solid: FAB-MS m/z=641 (M+H),high-resolution FAB-MS m/z calcd for C₃₀ H₄₅ N₂ O₉ S₂ 641.2567 (M+H),found 641.2568.

Part B. Preparation of N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-((2-hydroxymethyl-1,3-dihydroxyprop-2-yl)methyl!sulfonyl!propanamide

A mixture of the sulfide (0.20 g, 0.31 mmol) from Part A, and oxone(0.45 g, 0.73 mmol), in methanol (4.00 mL) and water (1.00 mL) wasstirred at 10°C. for 1.5 hours and then filtered. The filtrate wasconcentrated under reduced pressure, and the residue was partitionedbetween ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate(20 mL). The organic phase was washed with water (2×25 mL), dried (Na₂SO₄), and concentrated. The resulting residue was purified by flashcolumn chromatography on silica gel eluting with 4% methanol in ethylacetate to give the desired sulfone product (0.12 g, 57%) as a whiteamorphous powder: Rt=18.4 min; FAB-MS m/z=673 (M+H), high-resolutionFAB-MS m/z calcd for C₃₀ H₄₅ N₂ O₁₁ S₂ 673.2465 (M+H), found 673.2481.

EXAMPLE 74

Following the procedures of the previous Examples, the compounds setforth in Tables 2 through 13 can be prepared.

                  TABLE 2                                                         ______________________________________                                         ##STR105##                                                                   Entry  R.sup.3        R.sup.4                                                 ______________________________________                                        1      isobutyl       2-methyl-1,3-benzodioxol-5-yl                           2      isobutyl       2-methyl-1,3-benzodioxol-5-yl                           3      cyclopentylmethyl                                                                            2-methyl-1,3-benzodioxol-5-yl                           4      cyclohexylmethyl                                                                             2-methyl-1,3-benzodioxol-5-yl                           5      cyclopentylmethyl                                                                            1,3-benzodioxol-5-yl                                    6      cyclohexylmethyl                                                                             1,3-benzodioxol-5-yl                                    7      cyclopentylmethyl                                                                            benzofuran-5-yl                                         8      cyclohexylmethyl                                                                             benzofuran-5-yl                                         9      cyclopentylmethyl                                                                            2,3-dihydrobenzofuran-5-yl                              10     cyclohexylmethyl                                                                             2,3-dihydrobenzofuran-5-yl                              11     isobutyl       1,3-benzodioxol-5-yl                                    12     isobutyl       benzofuran-5-yl                                         13     isobutyl       2,3-dihydrobenzofuran-5-yl                              14     isobutyl       1,4-benzodioxan-6-yl                                    15     isoamyl        1,3-benzodioxol-5-yl                                    16     isoamyl        2,3-dihydrobenzofuran-5-yl                              17     isoamyl        1,4-benzodioxan-6-yl                                    18     isobutyl       benzothiazol-6-yl                                       19     isobutyl       2-amino-benzothiazol-6-yl                               20     isobutyl       benzoxazol-5-yl                                         21     cyclopentylmethyl                                                                            2,2-fluoro-1,3-benzodioxol-5-yl                         22     cyclohexylmethyl                                                                             2,2-fluoro-1,3-benzodioxol-5-yl                         ______________________________________                                    

                                      TABLE 3A                                    __________________________________________________________________________     ##STR106##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR107##                                                                                ##STR108##                                                                                 ##STR109##                                                                                 ##STR110##                              ##STR111##                                                                                ##STR112##                                                                                 ##STR113##                                                                                 ##STR114##                              ##STR115##                                                                                ##STR116##                                                                                 ##STR117##                                                                                 ##STR118##                              ##STR119##                                                                                ##STR120##                                                                                 ##STR121##                                                                                 ##STR122##                              ##STR123##                                                                                ##STR124##                                                                                 ##STR125##                                                                                 ##STR126##                              ##STR127##                                                                                ##STR128##                                                                                 ##STR129##                                                                                 ##STR130##                              ##STR131##                                                                                ##STR132##                                                                                 ##STR133##                                                                                 ##STR134##                             __________________________________________________________________________

                                      TABLE 3B                                    __________________________________________________________________________     ##STR135##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR136##                                                                                ##STR137##                                                                                 ##STR138##                                                                                 ##STR139##                              ##STR140##                                                                                ##STR141##                                                                                 ##STR142##                                                                                 ##STR143##                              ##STR144##                                                                                ##STR145##                                                                                 ##STR146##                                                                                 ##STR147##                              ##STR148##                                                                                ##STR149##                                                                                 ##STR150##                                                                                 ##STR151##                              ##STR152##                                                                                ##STR153##                                                                                 ##STR154##                                                                                 ##STR155##                              ##STR156##                                                                                ##STR157##                                                                                 ##STR158##                                                                                 ##STR159##                              ##STR160##                                                                                ##STR161##                                                                                 ##STR162##                                                                                 ##STR163##                             __________________________________________________________________________

                                      TABLE 3C                                    __________________________________________________________________________     ##STR164##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR165##                                                                                    ##STR166##                                                                                   ##STR167##                                     ##STR168##                                                                                    ##STR169##                                                                                   ##STR170##                                     ##STR171##                                                                                    ##STR172##                                                                                   ##STR173##                                     ##STR174##                                                                                    ##STR175##                                                                                   ##STR176##                                     ##STR177##                                                                                    ##STR178##                                                                                   ##STR179##                                     ##STR180##                                                                                    ##STR181##                                                                                   ##STR182##                                     ##STR183##                                                                                    ##STR184##                                                                                   ##STR185##                                     ##STR186##                                                                                    ##STR187##                                                                                   ##STR188##                                    __________________________________________________________________________

                                      TABLE 3D                                    __________________________________________________________________________     ##STR189##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR190##                                                                                 ##STR191##                                                                                 ##STR192##                                          ##STR193##                                                                                 ##STR194##                                                                                 ##STR195##                                          ##STR196##                                                                                 ##STR197##                                                                                 ##STR198##                                          ##STR199##                                                                                 ##STR200##                                                                                 ##STR201##                                          ##STR202##                                                                                 ##STR203##                                                                                 ##STR204##                                          ##STR205##                                                                                 ##STR206##                                                                                 ##STR207##                                          ##STR208##                                                                                 ##STR209##                                                                                 ##STR210##                                          ##STR211##                                                                                 ##STR212##                                                                                 ##STR213##                                         __________________________________________________________________________

                                      TABLE 3E                                    __________________________________________________________________________     ##STR214##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR215##                                                                               ##STR216##                                                                                 ##STR217##                                                                                 ##STR218##                               ##STR219##                                                                               ##STR220##                                                                                 ##STR221##                                                                                 ##STR222##                               ##STR223##                                                                               ##STR224##                                                                                 ##STR225##                                                                                 ##STR226##                               ##STR227##                                                                               ##STR228##                                                                                 ##STR229##                                                                                 ##STR230##                               ##STR231##                                                                               ##STR232##                                                                                 ##STR233##                                                                                 ##STR234##                               ##STR235##                                                                               ##STR236##                                                                                 ##STR237##                                                                                 ##STR238##                              __________________________________________________________________________

                                      TABLE 3F                                    __________________________________________________________________________     ##STR239##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR240##                                                                                    ##STR241##                                                                                    ##STR242##                                    ##STR243##                                                                                    ##STR244##                                                                                    ##STR245##                                    ##STR246##                                                                                    ##STR247##                                                                                    ##STR248##                                    ##STR249##                                                                                    ##STR250##                                                                                    ##STR251##                                    ##STR252##                                                                                    ##STR253##                                                                                    ##STR254##                                    ##STR255##                                                                                    ##STR256##                                                                                    ##STR257##                                    ##STR258##                                                                                    ##STR259##                                                                                    ##STR260##                                    ##STR261##                                                                                    ##STR262##                                                                                    ##STR263##                                   __________________________________________________________________________

                                      TABLE 3G                                    __________________________________________________________________________     ##STR264##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR265##                                                                                ##STR266##                                                                                 ##STR267##                                                                                 ##STR268##                              ##STR269##                                                                                ##STR270##                                                                                 ##STR271##                                                                                 ##STR272##                              ##STR273##                                                                                ##STR274##                                                                                 ##STR275##                                                                                 ##STR276##                              ##STR277##                                                                                ##STR278##                                                                                            ##STR279##                                ##STR280##                                                                                ##STR281##                                                                                            ##STR282##                                ##STR283##                                                                                ##STR284##                                                                                            ##STR285##                                ##STR286##                                                                                ##STR287##                                                                                            ##STR288##                               __________________________________________________________________________

                                      TABLE 3H                                    __________________________________________________________________________     ##STR289##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR290##                                                                                   ##STR291##                                                                                   ##STR292##                                      ##STR293##                                                                                   ##STR294##                                                                                   ##STR295##                                      ##STR296##                                                                                   ##STR297##                                                                                   ##STR298##                                      ##STR299##                                                                                   ##STR300##                                                                                   ##STR301##                                      ##STR302##                                                                                   ##STR303##                                                                                   ##STR304##                                      ##STR305##                                                                                   ##STR306##                                                                                   ##STR307##                                     __________________________________________________________________________

                                      TABLE 4A                                    __________________________________________________________________________     ##STR308##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR309##                                                                                ##STR310##                                                                                 ##STR311##                                                                                 ##STR312##                              ##STR313##                                                                                ##STR314##                                                                                 ##STR315##                                                                                 ##STR316##                              ##STR317##                                                                                ##STR318##                                                                                 ##STR319##                                                                                 ##STR320##                              ##STR321##                                                                                ##STR322##                                                                                 ##STR323##                                                                                 ##STR324##                              ##STR325##                                                                                ##STR326##                                                                                 ##STR327##                                                                                 ##STR328##                              ##STR329##                                                                                ##STR330##                                                                                 ##STR331##                                                                                 ##STR332##                              ##STR333##                                                                                ##STR334##                                                                                 ##STR335##                                                                                 ##STR336##                             __________________________________________________________________________

                                      TABLE 4B                                    __________________________________________________________________________     ##STR337##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR338##                                                                                ##STR339##                                                                                 ##STR340##                                                                                 ##STR341##                              ##STR342##                                                                                ##STR343##                                                                                 ##STR344##                                                                                 ##STR345##                              ##STR346##                                                                                ##STR347##                                                                                 ##STR348##                                                                                 ##STR349##                              ##STR350##                                                                                ##STR351##                                                                                 ##STR352##                                                                                 ##STR353##                              ##STR354##                                                                                ##STR355##                                                                                 ##STR356##                                                                                 ##STR357##                              ##STR358##                                                                                ##STR359##                                                                                 ##STR360##                                                                                 ##STR361##                              ##STR362##                                                                                ##STR363##                                                                                 ##STR364##                                                                                 ##STR365##                             __________________________________________________________________________

                                      TABLE 4C                                    __________________________________________________________________________     ##STR366##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR367##                                                                                    ##STR368##                                                                                   ##STR369##                                     ##STR370##                                                                                    ##STR371##                                                                                   ##STR372##                                     ##STR373##                                                                                    ##STR374##                                                                                   ##STR375##                                     ##STR376##                                                                                    ##STR377##                                                                                   ##STR378##                                     ##STR379##                                                                                    ##STR380##                                                                                   ##STR381##                                     ##STR382##                                                                                    ##STR383##                                                                                   ##STR384##                                     ##STR385##                                                                                    ##STR386##                                                                                   ##STR387##                                     ##STR388##                                                                                    ##STR389##                                                                                   ##STR390##                                    __________________________________________________________________________

                                      TABLE 4D                                    __________________________________________________________________________     ##STR391##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR392##                                                                                ##STR393##                                                                                ##STR394##                                            ##STR395##                                                                                ##STR396##                                                                                ##STR397##                                            ##STR398##                                                                                ##STR399##                                                                                ##STR400##                                            ##STR401##                                                                                ##STR402##                                                                                ##STR403##                                            ##STR404##                                                                                ##STR405##                                                                                ##STR406##                                            ##STR407##                                                                                ##STR408##                                                                                ##STR409##                                            ##STR410##                                                                                ##STR411##                                                                                ##STR412##                                            ##STR413##                                                                                ##STR414##                                                                                ##STR415##                                           __________________________________________________________________________

                                      TABLE 4E                                    __________________________________________________________________________     ##STR416##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR417##                                                                               ##STR418##                                                                                ##STR419##                                                                                ##STR420##                                 ##STR421##                                                                               ##STR422##                                                                                ##STR423##                                                                                ##STR424##                                 ##STR425##                                                                               ##STR426##                                                                                ##STR427##                                                                                ##STR428##                                 ##STR429##                                                                               ##STR430##                                                                                ##STR431##                                                                                ##STR432##                                 ##STR433##                                                                               ##STR434##                                                                                ##STR435##                                                                                ##STR436##                                 ##STR437##                                                                               ##STR438##                                                                                ##STR439##                                                                                ##STR440##                                __________________________________________________________________________

                                      TABLE 4F                                    __________________________________________________________________________     ##STR441##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR442##                                                                                    ##STR443##                                                                                    ##STR444##                                    ##STR445##                                                                                    ##STR446##                                                                                    ##STR447##                                    ##STR448##                                                                                    ##STR449##                                                                                    ##STR450##                                    ##STR451##                                                                                    ##STR452##                                                                                    ##STR453##                                    ##STR454##                                                                                    ##STR455##                                                                                    ##STR456##                                    ##STR457##                                                                                    ##STR458##     H.sub.2 NCH.sub.2.CH.sub.2                     ##STR459##                                                                                    ##STR460##     H.sub.2 NCH.sub.2.(CH.sub.2).sub.2             ##STR461##                                                                                    ##STR462##     H.sub.2 NCH.sub.2.(CH.sub.2).sub.3            __________________________________________________________________________

                                      TABLE 4G                                    __________________________________________________________________________     ##STR463##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR464##                                                                                ##STR465##                                                                                 ##STR466##                                                                                 ##STR467##                              ##STR468##                                                                                ##STR469##                                                                                 ##STR470##                                                                                 ##STR471##                              ##STR472##                                                                                ##STR473##                                                                                 ##STR474##                                                                                 ##STR475##                              ##STR476##                                                                                    ##STR477##                                                                                    ##STR478##                                    ##STR479##                                                                                    ##STR480##                                                                                    ##STR481##                                    ##STR482##                                                                                    ##STR483##                                                                                    ##STR484##                                    ##STR485##                                                                                    ##STR486##                                                                                    ##STR487##                                   __________________________________________________________________________

                                      TABLE 4H                                    __________________________________________________________________________     ##STR488##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR489##                                                                                   ##STR490##                                                                                   ##STR491##                                      ##STR492##                                                                                   ##STR493##                                                                                   ##STR494##                                      ##STR495##                                                                                   ##STR496##                                                                                   ##STR497##                                      ##STR498##                                                                                   ##STR499##                                                                                   ##STR500##                                      ##STR501##                                                                                   ##STR502##                                                                                   ##STR503##                                      ##STR504##                                                                                   ##STR505##                                                                                   ##STR506##                                     __________________________________________________________________________

                                      TABLE 5A                                    __________________________________________________________________________     ##STR507##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR508##                                                                                ##STR509##                                                                                 ##STR510##                                                                                 ##STR511##                              ##STR512##                                                                                ##STR513##                                                                                 ##STR514##                                                                                 ##STR515##                              ##STR516##                                                                                ##STR517##                                                                                 ##STR518##                                                                                 ##STR519##                              ##STR520##                                                                                ##STR521##                                                                                 ##STR522##                                                                                 ##STR523##                              ##STR524##                                                                                ##STR525##                                                                                 ##STR526##                                                                                 ##STR527##                              ##STR528##                                                                                ##STR529##                                                                                 ##STR530##                                                                                 ##STR531##                              ##STR532##                                                                                ##STR533##                                                                                 ##STR534##                                                                                 ##STR535##                             __________________________________________________________________________

                                      TABLE 5B                                    __________________________________________________________________________     ##STR536##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR537##                                                                                ##STR538##                                                                                 ##STR539##                                                                                 ##STR540##                              ##STR541##                                                                                ##STR542##                                                                                 ##STR543##                                                                                 ##STR544##                              ##STR545##                                                                                ##STR546##                                                                                 ##STR547##                                                                                 ##STR548##                              ##STR549##                                                                                ##STR550##                                                                                 ##STR551##                                                                                 ##STR552##                              ##STR553##                                                                                ##STR554##                                                                                 ##STR555##                                                                                 ##STR556##                              ##STR557##                                                                                ##STR558##                                                                                 ##STR559##                                                                                 ##STR560##                              ##STR561##                                                                                ##STR562##                                                                                 ##STR563##                                                                                 ##STR564##                             __________________________________________________________________________

                                      TABLE 5C                                    __________________________________________________________________________     ##STR565##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR566##                                                                                    ##STR567##                                                                                   ##STR568##                                     ##STR569##                                                                                    ##STR570##                                                                                   ##STR571##                                     ##STR572##                                                                                    ##STR573##                                                                                   ##STR574##                                     ##STR575##                                                                                    ##STR576##                                                                                   ##STR577##                                     ##STR578##                                                                                    ##STR579##                                                                                   ##STR580##                                     ##STR581##                                                                                    ##STR582##                                                                                   ##STR583##                                     ##STR584##                                                                                    ##STR585##                                                                                   ##STR586##                                     ##STR587##                                                                                    ##STR588##                                                                                   ##STR589##                                    __________________________________________________________________________

                                      TABLE 5D                                    __________________________________________________________________________     ##STR590##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR591##                                                                                 ##STR592##                                                                                 ##STR593##                                          ##STR594##                                                                                 ##STR595##                                                                                 ##STR596##                                          ##STR597##                                                                                 ##STR598##                                                                                 ##STR599##                                          ##STR600##                                                                                 ##STR601##                                                                                 ##STR602##                                          ##STR603##                                                                                 ##STR604##                                                                                 ##STR605##                                          ##STR606##                                                                                 ##STR607##                                                                                 ##STR608##                                          ##STR609##                                                                                 ##STR610##                                                                                 ##STR611##                                          ##STR612##                                                                                 ##STR613##                                                                                 ##STR614##                                         __________________________________________________________________________

                                      TABLE 5E                                    __________________________________________________________________________     ##STR615##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR616##                                                                               ##STR617##                                                                                ##STR618##                                                                                ##STR619##                                 ##STR620##                                                                               ##STR621##                                                                                ##STR622##                                                                                ##STR623##                                 ##STR624##                                                                               ##STR625##                                                                                ##STR626##                                                                                ##STR627##                                 ##STR628##                                                                               ##STR629##                                                                                ##STR630##                                                                                ##STR631##                                 ##STR632##                                                                               ##STR633##                                                                                ##STR634##                                                                                ##STR635##                                 ##STR636##                                                                               ##STR637##                                                                                ##STR638##                                                                                ##STR639##                                __________________________________________________________________________

                                      TABLE 5F                                    __________________________________________________________________________     ##STR640##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR641##                                                                                    ##STR642##                                                                                    ##STR643##                                    ##STR644##                                                                                    ##STR645##                                                                                    ##STR646##                                    ##STR647##                                                                                    ##STR648##                                                                                    ##STR649##                                    ##STR650##                                                                                    ##STR651##                                                                                    ##STR652##                                    ##STR653##                                                                                    ##STR654##                                                                                    ##STR655##                                    ##STR656##                                                                                    ##STR657##     H.sub.2 NCH.sub.2.CH.sub.2                     ##STR658##                                                                                    ##STR659##     H.sub.2 NCH.sub.2.(CH.sub.2).sub.2             ##STR660##                                                                                    ##STR661##     H.sub.2 NCH.sub.2.(CH.sub.2).sub.3        

                                      TABLE 5G                                    __________________________________________________________________________     ##STR662##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR663##                                                                                ##STR664##                                                                                 ##STR665##                                                                                 ##STR666##                              ##STR667##                                                                                ##STR668##                                                                                 ##STR669##                                                                                 ##STR670##                              ##STR671##                                                                                ##STR672##                                                                                 ##STR673##                                                                                 ##STR674##                              ##STR675##                                                                                ##STR676##                                                                                            ##STR677##                                ##STR678##                                                                                ##STR679##                                                                                            ##STR680##                                ##STR681##                                                                                ##STR682##                                                                                            ##STR683##                                ##STR684##                                                                                ##STR685##                                                                                            ##STR686##                               __________________________________________________________________________

                                      TABLE 5H                                    __________________________________________________________________________     ##STR687##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR688##                                                                                   ##STR689##                                                                                   ##STR690##                                      ##STR691##                                                                                   ##STR692##                                                                                   ##STR693##                                      ##STR694##                                                                                   ##STR695##                                                                                   ##STR696##                                      ##STR697##                                                                                   ##STR698##                                                                                   ##STR699##                                      ##STR700##                                                                                   ##STR701##                                                                                   ##STR702##                                      ##STR703##                                                                                   ##STR704##                                                                                   ##STR705##                                     __________________________________________________________________________

                                      TABLE 6A                                    __________________________________________________________________________     ##STR706##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR707##                                                                                ##STR708##                                                                                 ##STR709##                                                                                 ##STR710##                              ##STR711##                                                                                ##STR712##                                                                                 ##STR713##                                                                                 ##STR714##                              ##STR715##                                                                                ##STR716##                                                                                 ##STR717##                                                                                 ##STR718##                              ##STR719##                                                                                ##STR720##                                                                                 ##STR721##                                                                                 ##STR722##                              ##STR723##                                                                                ##STR724##                                                                                 ##STR725##                                                                                 ##STR726##                              ##STR727##                                                                                ##STR728##                                                                                 ##STR729##                                                                                 ##STR730##                              ##STR731##                                                                                ##STR732##                                                                                 ##STR733##                                                                                 ##STR734##                             __________________________________________________________________________

                                      TABLE 6B                                    __________________________________________________________________________     ##STR735##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR736##                                                                                ##STR737##                                                                                 ##STR738##                                                                                 ##STR739##                              ##STR740##                                                                                ##STR741##                                                                                 ##STR742##                                                                                 ##STR743##                              ##STR744##                                                                                ##STR745##                                                                                 ##STR746##                                                                                 ##STR747##                              ##STR748##                                                                                ##STR749##                                                                                 ##STR750##                                                                                 ##STR751##                              ##STR752##                                                                                ##STR753##                                                                                 ##STR754##                                                                                 ##STR755##                              ##STR756##                                                                                ##STR757##                                                                                 ##STR758##                                                                                 ##STR759##                              ##STR760##                                                                                ##STR761##                                                                                 ##STR762##                                                                                 ##STR763##                             __________________________________________________________________________

                                      TABLE 6C                                    __________________________________________________________________________     ##STR764##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR765##                                                                                   ##STR766##                                                                                   ##STR767##                                      ##STR768##                                                                                   ##STR769##                                                                                   ##STR770##                                      ##STR771##                                                                                   ##STR772##                                                                                   ##STR773##                                      ##STR774##                                                                                   ##STR775##                                                                                   ##STR776##                                      ##STR777##                                                                                   ##STR778##                                                                                   ##STR779##                                      ##STR780##                                                                                   ##STR781##                                                                                   ##STR782##                                      ##STR783##                                                                                   ##STR784##                                                                                   ##STR785##                                      ##STR786##                                                                                   ##STR787##                                                                                   ##STR788##                                     __________________________________________________________________________

                                      TABLE 6D                                    __________________________________________________________________________     ##STR789##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR790##                                                                                ##STR791##                                                                                ##STR792##                                            ##STR793##                                                                                ##STR794##                                                                                ##STR795##                                            ##STR796##                                                                                ##STR797##                                                                                ##STR798##                                            ##STR799##                                                                                ##STR800##                                                                                ##STR801##                                            ##STR802##                                                                                ##STR803##                                                                                ##STR804##                                            ##STR805##                                                                                ##STR806##                                                                                ##STR807##                                            ##STR808##                                                                                ##STR809##                                                                                ##STR810##                                            ##STR811##                                                                                ##STR812##                                                                                ##STR813##                                           __________________________________________________________________________

                                      TABLE 6E                                    __________________________________________________________________________     ##STR814##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR815##                                                                               ##STR816##                                                                                ##STR817##                                                                                ##STR818##                                 ##STR819##                                                                               ##STR820##                                                                                ##STR821##                                                                                ##STR822##                                 ##STR823##                                                                               ##STR824##                                                                                ##STR825##                                                                                ##STR826##                                 ##STR827##                                                                               ##STR828##                                                                                ##STR829##                                                                                ##STR830##                                 ##STR831##                                                                               ##STR832##                                                                                ##STR833##                                                                                ##STR834##                                 ##STR835##                                                                               ##STR836##                                                                                ##STR837##                                                                                ##STR838##                                __________________________________________________________________________

                                      TABLE 6F                                    __________________________________________________________________________     ##STR839##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR840##                                                                                    ##STR841##                                                                                    ##STR842##                                    ##STR843##                                                                                    ##STR844##                                                                                    ##STR845##                                    ##STR846##                                                                                    ##STR847##                                                                                    ##STR848##                                    ##STR849##                                                                                    ##STR850##                                                                                    ##STR851##                                    ##STR852##                                                                                    ##STR853##                                                                                    ##STR854##                                    ##STR855##                                                                                    ##STR856##                                                                                    ##STR857##                                    ##STR858##                                                                                    ##STR859##                                                                                    ##STR860##                                    ##STR861##                                                                                    ##STR862##                                                                                    ##STR863##                                   __________________________________________________________________________

                                      TABLE 6G                                    __________________________________________________________________________     ##STR864##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR865##                                                                                ##STR866##                                                                                 ##STR867##                                                                                 ##STR868##                              ##STR869##                                                                                ##STR870##                                                                                 ##STR871##                                                                                 ##STR872##                              ##STR873##                                                                                ##STR874##                                                                                 ##STR875##                                                                                 ##STR876##                              ##STR877##                                                                                    ##STR878##                                                                                     ##STR879##                                   ##STR880##                                                                                    ##STR881##                                                                                     ##STR882##                                   ##STR883##                                                                                    ##STR884##                                                                                     ##STR885##                                   ##STR886##                                                                                    ##STR887##                                                                                     ##STR888##                                  __________________________________________________________________________

                                      TABLE 6H                                    __________________________________________________________________________     ##STR889##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR890##                                                                                   ##STR891##                                                                                   ##STR892##                                      ##STR893##                                                                                   ##STR894##                                                                                   ##STR895##                                      ##STR896##                                                                                   ##STR897##                                                                                   ##STR898##                                      ##STR899##                                                                                   ##STR900##                                                                                   ##STR901##                                      ##STR902##                                                                                   ##STR903##                                                                                   ##STR904##                                      ##STR905##                                                                                   ##STR906##                                                                                   ##STR907##                                     __________________________________________________________________________

                                      TABLE 6H                                    __________________________________________________________________________     ##STR908##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR909##                                                                                ##STR910##                                                                                 ##STR911##                                                                                 ##STR912##                              ##STR913##                                                                                ##STR914##                                                                                 ##STR915##                                                                                 ##STR916##                              ##STR917##                                                                                ##STR918##                                                                                 ##STR919##                                                                                 ##STR920##                              ##STR921##                                                                                ##STR922##                                                                                 ##STR923##                                                                                 ##STR924##                              ##STR925##                                                                                ##STR926##                                                                                 ##STR927##                                                                                 ##STR928##                              ##STR929##                                                                                ##STR930##                                                                                 ##STR931##                                                                                 ##STR932##                              ##STR933##                                                                                ##STR934##                                                                                 ##STR935##                                                                                 ##STR936##                             __________________________________________________________________________

                                      TABLE 7B                                    __________________________________________________________________________     ##STR937##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR938##                                                                                ##STR939##                                                                                 ##STR940##                                                                                 ##STR941##                              ##STR942##                                                                                ##STR943##                                                                                 ##STR944##                                                                                 ##STR945##                              ##STR946##                                                                                ##STR947##                                                                                 ##STR948##                                                                                 ##STR949##                              ##STR950##                                                                                ##STR951##                                                                                 ##STR952##                                                                                 ##STR953##                              ##STR954##                                                                                ##STR955##                                                                                 ##STR956##                                                                                 ##STR957##                              ##STR958##                                                                                ##STR959##                                                                                 ##STR960##                                                                                 ##STR961##                              ##STR962##                                                                                ##STR963##                                                                                 ##STR964##                                                                                 ##STR965##                             __________________________________________________________________________

                                      TABLE 7C                                    __________________________________________________________________________     ##STR966##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR967##                                                                                   ##STR968##                                                                                   ##STR969##                                      ##STR970##                                                                                   ##STR971##                                                                                   ##STR972##                                      ##STR973##                                                                                   ##STR974##                                                                                   ##STR975##                                      ##STR976##                                                                                   ##STR977##                                                                                   ##STR978##                                      ##STR979##                                                                                   ##STR980##                                                                                   ##STR981##                                      ##STR982##                                                                                   ##STR983##                                                                                   ##STR984##                                      ##STR985##                                                                                   ##STR986##                                                                                   ##STR987##                                      ##STR988##                                                                                   ##STR989##                                                                                   ##STR990##                                     __________________________________________________________________________

                                      TABLE 7D                                    __________________________________________________________________________     ##STR991##                                                                   Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR992##                                                                                ##STR993##                                                                                ##STR994##                                            ##STR995##                                                                                ##STR996##                                                                                ##STR997##                                            ##STR998##                                                                                ##STR999##                                                                                ##STR1000##                                           ##STR1001##                                                                               ##STR1002##                                                                               ##STR1003##                                           ##STR1004##                                                                               ##STR1005##                                                                               ##STR1006##                                           ##STR1007##                                                                               ##STR1008##                                                                               ##STR1009##                                           ##STR1010##                                                                               ##STR1011##                                                                               ##STR1012##                                           ##STR1013##                                                                               ##STR1014##                                                                               ##STR1015##                                          __________________________________________________________________________

                                      TABLE 7E                                    __________________________________________________________________________     ##STR1016##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1017##                                                                              ##STR1018##                                                                                ##STR1019##                                                                                ##STR1020##                              ##STR1021##                                                                              ##STR1022##                                                                                ##STR1023##                                                                                ##STR1024##                              ##STR1025##                                                                              ##STR1026##                                                                                ##STR1027##                                                                                ##STR1028##                              ##STR1029##                                                                              ##STR1030##                                                                                ##STR1031##                                                                                ##STR1032##                              ##STR1033##                                                                              ##STR1034##                                                                                ##STR1035##                                                                                ##STR1036##                              ##STR1037##                                                                              ##STR1038##                                                                                ##STR1039##                                                                                ##STR1040##                             __________________________________________________________________________

                                      TABLE 7F                                    __________________________________________________________________________     ##STR1041##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1042##                                                                                   ##STR1043##                                                                                   ##STR1044##                                   ##STR1045##                                                                                   ##STR1046##                                                                                   ##STR1047##                                   ##STR1048##                                                                                   ##STR1049##                                                                                   ##STR1050##                                   ##STR1051##                                                                                   ##STR1052##                                                                                   ##STR1053##                                   ##STR1054##                                                                                   ##STR1055##                                                                                   ##STR1056##                                   ##STR1057##                                                                                   ##STR1058##                                                                                   ##STR1059##                                   ##STR1060##                                                                                   ##STR1061##                                                                                   ##STR1062##                                   ##STR1063##                                                                                   ##STR1064##                                                                                   ##STR1065##                                  __________________________________________________________________________

                                      TABLE 7G                                    __________________________________________________________________________     ##STR1066##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1067##                                                                               ##STR1068##                                                                                ##STR1069##                                                                                ##STR1070##                             ##STR1071##                                                                               ##STR1072##                                                                                ##STR1073##                                                                                ##STR1074##                             ##STR1075##                                                                               ##STR1076##                                                                                ##STR1077##                                                                                ##STR1078##                             ##STR1079##                                                                                  ##STR1080##                                                                                      ##STR1081##                                 ##STR1082##                                                                                  ##STR1083##                                                                                      ##STR1084##                                 ##STR1085##                                                                                  ##STR1086##                                                                                      ##STR1087##                                 ##STR1088##                                                                                  ##STR1089##                                                                                      ##STR1090##                                __________________________________________________________________________

                                      TABLE 7H                                    __________________________________________________________________________     ##STR1091##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1092##                                                                                  ##STR1093##                                                                                  ##STR1094##                                     ##STR1095##                                                                                  ##STR1096##                                                                                  ##STR1097##                                     ##STR1098##                                                                                  ##STR1099##                                                                                  ##STR1100##                                     ##STR1101##                                                                                  ##STR1102##                                                                                  ##STR1103##                                     ##STR1104##                                                                                  ##STR1105##                                                                                  ##STR1106##                                     ##STR1107##                                                                                  ##STR1108##                                                                                  ##STR1109##                                    __________________________________________________________________________

                                      TABLE 8A                                    __________________________________________________________________________     ##STR1110##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1111##                                                                               ##STR1112##                                                                                ##STR1113##                                                                                ##STR1114##                             ##STR1115##                                                                               ##STR1116##                                                                                ##STR1117##                                                                                ##STR1118##                             ##STR1119##                                                                               ##STR1120##                                                                                ##STR1121##                                                                                ##STR1122##                             ##STR1123##                                                                               ##STR1124##                                                                                ##STR1125##                                                                                ##STR1126##                             ##STR1127##                                                                               ##STR1128##                                                                                ##STR1129##                                                                                ##STR1130##                             ##STR1131##                                                                               ##STR1132##                                                                                ##STR1133##                                                                                ##STR1134##                             ##STR1135##                                                                               ##STR1136##                                                                                ##STR1137##                                                                                ##STR1138##                            __________________________________________________________________________

                                      TABLE 8B                                    __________________________________________________________________________     ##STR1139##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1140##                                                                               ##STR1141##                                                                                ##STR1142##                                                                                ##STR1143##                             ##STR1144##                                                                               ##STR1145##                                                                                ##STR1146##                                                                                ##STR1147##                             ##STR1148##                                                                               ##STR1149##                                                                                ##STR1150##                                                                                ##STR1151##                             ##STR1152##                                                                               ##STR1153##                                                                                ##STR1154##                                                                                ##STR1155##                             ##STR1156##                                                                               ##STR1157##                                                                                ##STR1158##                                                                                ##STR1159##                             ##STR1160##                                                                               ##STR1161##                                                                                ##STR1162##                                                                                ##STR1163##                             ##STR1164##                                                                               ##STR1165##                                                                                ##STR1166##                                                                                ##STR1167##                            __________________________________________________________________________

                                      TABLE 8C                                    __________________________________________________________________________     ##STR1168##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1169##                                                                                   ##STR1170##                                                                                  ##STR1171##                                    ##STR1172##                                                                                   ##STR1173##                                                                                  ##STR1174##                                    ##STR1175##                                                                                   ##STR1176##                                                                                  ##STR1177##                                    ##STR1178##                                                                                   ##STR1179##                                                                                  ##STR1180##                                    ##STR1181##                                                                                   ##STR1182##                                                                                  ##STR1183##                                    ##STR1184##                                                                                   ##STR1185##                                                                                  ##STR1186##                                    ##STR1187##                                                                                   ##STR1188##                                                                                  ##STR1189##                                    ##STR1190##                                                                                   ##STR1191##                                                                                  ##STR1192##                                   __________________________________________________________________________

                                      TABLE 8D                                    __________________________________________________________________________     ##STR1193##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1194##                                                                               ##STR1195##                                                                               ##STR1196##                                           ##STR1197##                                                                               ##STR1198##                                                                               ##STR1199##                                           ##STR1200##                                                                               ##STR1201##                                                                               ##STR1202##                                           ##STR1203##                                                                               ##STR1204##                                                                               ##STR1205##                                           ##STR1206##                                                                               ##STR1207##                                                                               ##STR1208##                                           ##STR1209##                                                                               ##STR1210##                                                                               ##STR1211##                                           ##STR1212##                                                                               ##STR1213##                                                                               ##STR1214##                                           ##STR1215##                                                                               ##STR1216##                                                                               ##STR1217##                                          __________________________________________________________________________

                                      TABLE 8E                                    __________________________________________________________________________     ##STR1218##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1219##                                                                              ##STR1220##                                                                               ##STR1221##                                                                               ##STR1222##                                ##STR1223##                                                                              ##STR1224##                                                                               ##STR1225##                                                                               ##STR1226##                                ##STR1227##                                                                              ##STR1228##                                                                               ##STR1229##                                                                               ##STR1230##                                ##STR1231##                                                                              ##STR1232##                                                                               ##STR1233##                                                                               ##STR1234##                                ##STR1235##                                                                              ##STR1236##                                                                               ##STR1237##                                                                               ##STR1238##                                ##STR1239##                                                                              ##STR1240##                                                                               ##STR1241##                                                                               ##STR1242##                               __________________________________________________________________________

                                      TABLE 8F                                    __________________________________________________________________________     ##STR1243##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1244##                                                                                   ##STR1245##                                                                                   ##STR1246##                                   ##STR1247##                                                                                   ##STR1248##                                                                                   ##STR1249##                                   ##STR1250##                                                                                   ##STR1251##                                                                                   ##STR1252##                                   ##STR1253##                                                                                   ##STR1254##                                                                                   ##STR1255##                                   ##STR1256##                                                                                   ##STR1257##                                                                                   ##STR1258##                                   ##STR1259##                                                                                   ##STR1260##    H.sub.2 NCH.sub.2.CH.sub.2                     ##STR1261##                                                                                   ##STR1262##    H.sub.2 NCH.sub.2.(CH.sub.2).sub.2             ##STR1263##                                                                                   ##STR1264##    H.sub.2 NCH.sub.2.(CH.sub.2).sub.3            __________________________________________________________________________

                                      TABLE 8G                                    __________________________________________________________________________     ##STR1265##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1266##                                                                               ##STR1267##                                                                                ##STR1268##                                                                                ##STR1269##                             ##STR1270##                                                                               ##STR1271##                                                                                ##STR1272##                                                                                ##STR1273##                             ##STR1274##                                                                               ##STR1275##                                                                                ##STR1276##                                                                                ##STR1277##                             ##STR1278##                                                                                   ##STR1279##                                                                                   ##STR1280##                                   ##STR1281##                                                                                   ##STR1282##                                                                                   ##STR1283##                                   ##STR1284##                                                                                   ##STR1285##                                                                                   ##STR1286##                                   ##STR1287##                                                                                   ##STR1288##                                                                                   ##STR1289##                                  __________________________________________________________________________

                                      TABLE 8H                                    __________________________________________________________________________     ##STR1290##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1291##                                                                                  ##STR1292##                                                                                  ##STR1293##                                     ##STR1294##                                                                                  ##STR1295##                                                                                  ##STR1296##                                     ##STR1297##                                                                                  ##STR1298##                                                                                  ##STR1299##                                     ##STR1300##                                                                                  ##STR1301##                                                                                  ##STR1302##                                     ##STR1303##                                                                                  ##STR1304##                                                                                  ##STR1305##                                     ##STR1306##                                                                                  ##STR1307##                                                                                  ##STR1308##                                    __________________________________________________________________________

                                      TABLE 9A                                    __________________________________________________________________________     ##STR1309##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1310##                                                                               ##STR1311##                                                                                ##STR1312##                                                                                ##STR1313##                             ##STR1314##                                                                               ##STR1315##                                                                                ##STR1316##                                                                                ##STR1317##                             ##STR1318##                                                                               ##STR1319##                                                                                ##STR1320##                                                                                ##STR1321##                             ##STR1322##                                                                               ##STR1323##                                                                                ##STR1324##                                                                                ##STR1325##                             ##STR1326##                                                                               ##STR1327##                                                                                ##STR1328##                                                                                ##STR1329##                             ##STR1330##                                                                               ##STR1331##                                                                                ##STR1332##                                                                                ##STR1333##                             ##STR1334##                                                                               ##STR1335##                                                                                ##STR1336##                                                                                ##STR1337##                            __________________________________________________________________________

                                      TABLE 9B                                    __________________________________________________________________________     ##STR1338##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1339##                                                                               ##STR1340##                                                                                ##STR1341##                                                                                ##STR1342##                             ##STR1343##                                                                               ##STR1344##                                                                                ##STR1345##                                                                                ##STR1346##                             ##STR1347##                                                                               ##STR1348##                                                                                ##STR1349##                                                                                ##STR1350##                             ##STR1351##                                                                               ##STR1352##                                                                                ##STR1353##                                                                                ##STR1354##                             ##STR1355##                                                                               ##STR1356##                                                                                ##STR1357##                                                                                ##STR1358##                             ##STR1359##                                                                               ##STR1360##                                                                                ##STR1361##                                                                                ##STR1362##                             ##STR1363##                                                                               ##STR1364##                                                                                ##STR1365##                                                                                ##STR1366##                            __________________________________________________________________________

                                      TABLE 9C                                    __________________________________________________________________________     ##STR1367##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1368##                                                                                   ##STR1369##                                                                                  ##STR1370##                                    ##STR1371##                                                                                   ##STR1372##                                                                                  ##STR1373##                                    ##STR1374##                                                                                   ##STR1375##                                                                                  ##STR1376##                                    ##STR1377##                                                                                   ##STR1378##                                                                                  ##STR1379##                                    ##STR1380##                                                                                   ##STR1381##                                                                                  ##STR1382##                                    ##STR1383##                                                                                   ##STR1384##                                                                                  ##STR1385##                                    ##STR1386##                                                                                   ##STR1387##                                                                                  ##STR1388##                                    ##STR1389##                                                                                   ##STR1390##                                                                                  ##STR1391##                                   __________________________________________________________________________

                                      TABLE 9D                                    __________________________________________________________________________     ##STR1392##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1393##                                                                               ##STR1394##                                                                               ##STR1395##                                           ##STR1396##                                                                               ##STR1397##                                                                               ##STR1398##                                           ##STR1399##                                                                               ##STR1400##                                                                               ##STR1401##                                           ##STR1402##                                                                               ##STR1403##                                                                               ##STR1404##                                           ##STR1405##                                                                               ##STR1406##                                                                               ##STR1407##                                           ##STR1408##                                                                               ##STR1409##                                                                               ##STR1410##                                           ##STR1411##                                                                               ##STR1412##                                                                               ##STR1413##                                           ##STR1414##                                                                               ##STR1415##                                                                               ##STR1416##                                          __________________________________________________________________________

                                      TABLE 9E                                    __________________________________________________________________________     ##STR1417##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1418##                                                                              ##STR1419##                                                                                ##STR1420##                                                                                ##STR1421##                              ##STR1422##                                                                              ##STR1423##                                                                                ##STR1424##                                                                                ##STR1425##                              ##STR1426##                                                                              ##STR1427##                                                                                ##STR1428##                                                                                ##STR1429##                              ##STR1430##                                                                              ##STR1431##                                                                                ##STR1432##                                                                                ##STR1433##                              ##STR1434##                                                                              ##STR1435##                                                                                ##STR1436##                                                                                ##STR1437##                              ##STR1438##                                                                              ##STR1439##                                                                                ##STR1440##                                                                                ##STR1441##                             __________________________________________________________________________

                                      TABLE 9F                                    __________________________________________________________________________     ##STR1442##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1443##                                                                                   ##STR1444##                                                                                   ##STR1445##                                   ##STR1446##                                                                                   ##STR1447##                                                                                   ##STR1448##                                   ##STR1449##                                                                                   ##STR1450##                                                                                   ##STR1451##                                   ##STR1452##                                                                                   ##STR1453##                                                                                   ##STR1454##                                   ##STR1455##                                                                                   ##STR1456##                                                                                   ##STR1457##                                   ##STR1458##                                                                                   ##STR1459##    H.sub.2 NCH.sub.2.CH.sub.2                     ##STR1460##                                                                                   ##STR1461##    H.sub.2 NCH.sub.2.(CH.sub.2).sub.2             ##STR1462##                                                                                   ##STR1463##    H.sub.2 NCH.sub.2.(CH.sub.2).sub.3            __________________________________________________________________________

                                      TABLE 9G                                    __________________________________________________________________________     ##STR1464##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1465##                                                                              ##STR1466##                                                                               ##STR1467##                                                                               ##STR1468##                                ##STR1469##                                                                              ##STR1470##                                                                               ##STR1471##                                                                               ##STR1472##                                ##STR1473##                                                                              ##STR1474##                                                                               ##STR1475##                                                                               ##STR1476##                                ##STR1477##                                                                              ##STR1478##                                                                                        ##STR1479##                                   ##STR1480##                                                                              ##STR1481##                                                                                        ##STR1482##                                   ##STR1483##                                                                              ##STR1484##                                                                                        ##STR1485##                                   ##STR1486##                                                                              ##STR1487##                                                                                        ##STR1488##                                  __________________________________________________________________________

                                      TABLE 9H                                    __________________________________________________________________________     ##STR1489##                                                                  Entry                                                                             R.sup.5                                                                   __________________________________________________________________________     ##STR1490##                                                                                 ##STR1491##                                                                                 ##STR1492##                                       ##STR1493##                                                                                 ##STR1494##                                                                                 ##STR1495##                                       ##STR1496##                                                                                 ##STR1497##                                                                                 ##STR1498##                                       ##STR1499##                                                                                 ##STR1500##                                                                                 ##STR1501##                                       ##STR1502##                                                                                 ##STR1503##                                                                                 ##STR1504##                                       ##STR1505##                                                                                 ##STR1506##                                                                                 ##STR1507##                                      __________________________________________________________________________

                                      TABLE 10A                                   __________________________________________________________________________     ##STR1508##                                                                  Entry                                                                             R.sup.2                                                                   __________________________________________________________________________    (CH.sub.3).sub.2 CHCH.sub.2                                                                   (4-FC.sub.6 H.sub.5)CH.sub.2                                  CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           (naphth-2-yl)CH.sub.2                                         CH.sub.3 SCH.sub.2 CH.sub.2                                                                   C.sub.6 H.sub.11 CH.sub.2                                     C.sub.6 H.sub.5 CH.sub.2                                                                      C.sub.6 H.sub.5 SCH.sub.2                                     (4-CH.sub.3 OC.sub.6 H.sub.5)CH.sub.2                                                         (naphth-2-yl)SCH.sub.2                                        __________________________________________________________________________

                                      TABLE 10B                                   __________________________________________________________________________     ##STR1509##                                                                  Entry                                                                             R.sup.2                                                                   __________________________________________________________________________    (CH.sub.3).sub.2 CHCH.sub.2                                                                   (4-FC.sub.6 H.sub.5)CH.sub.2                                  CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                           (naphth-2-yl)CH.sub.2                                         CH.sub.3 SCH.sub.2 CH.sub.2                                                                   C.sub.6 H.sub.11 CH.sub.2                                     C.sub.6 H.sub.5 CH.sub.2                                                                      C.sub.6 H.sub.5 SCH.sub.2                                     (4-CH.sub.3 OC.sub.6 H.sub.5)CH.sub.2                                                         (naphth-2-yl)SCH.sub.2                                        __________________________________________________________________________

                                      TABLE 10C                                   __________________________________________________________________________     ##STR1510##                                                                  Entry                                                                             R.sup.2                                                                   __________________________________________________________________________    (CH.sub.3).sub.2 CHCH.sub.2                                                                    (4-FC.sub.6 H.sub.5)CH.sub.2                                 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                            (naphth-2-yl)CH.sub.2                                        CH.sub.3 SCH.sub.2 CH.sub.2                                                                    C.sub.6 H.sub.11 CH.sub.2                                    C.sub.6 H.sub.5 CH.sub.2                                                                       C.sub.6 H.sub.5 SCH.sub.2                                    (4-CH.sub.3 OC.sub.6 H.sub.5)CH.sub.2                                                          (naphth-2-yl)SCH.sub.2                                       __________________________________________________________________________

                                      TABLE 10D                                   __________________________________________________________________________     ##STR1511##                                                                  Entry                                                                             R.sup.2                                                                   __________________________________________________________________________    (CH.sub.3).sub.2 CHCH.sub.2                                                                    (4-FC.sub.6 H.sub.5)CH.sub.2                                 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                            (naphth-2-yl)CH.sub.2                                        CH.sub.3 SCH.sub.2 CH.sub.2                                                                    C.sub.6 H.sub.11 CH.sub.2                                    C.sub.6 H.sub.5 CH.sub.2                                                                       C.sub.6 H.sub.5 SCH.sub.2                                    (4-CH.sub.3 OC.sub.6 H.sub.5)CH.sub.2                                                          (naphth-2-yl)SCH.sub.2                                       __________________________________________________________________________

                                      TABLE 10E                                   __________________________________________________________________________     ##STR1512##                                                                  Entry                                                                             R.sup.2                                                                   __________________________________________________________________________    (CH.sub.3).sub.2 CHCH.sub.2                                                                    (4-FC.sub.6 H.sub.5)CH.sub.2                                 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                            (naphth-2-yl)CH.sub.2                                        CH.sub.3 SCH.sub.2 CH.sub.2                                                                    C.sub.6 H.sub.11 CH.sub.2                                    C.sub.6 H.sub.5 CH.sub.2                                                                       C.sub.6 H.sub.5 SCH.sub.2                                    (4-CH.sub.3 OC.sub.6 H.sub.5)CH.sub.2                                                          (naphth-2-yl)SCH.sub.2                                       __________________________________________________________________________

                                      TABLE 10F                                   __________________________________________________________________________     ##STR1513##                                                                  Entry                                                                             R.sup.2                                                                   __________________________________________________________________________    (CH.sub.3).sub.2 CHCH.sub.2                                                                    (4-FC.sub.6 H.sub.5)CH.sub.2                                 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                            (naphth-2-yl)CH.sub.2                                        CH.sub.3 SCH.sub.2 CH.sub.2                                                                    C.sub.6 H.sub.11 CH.sub.2                                    C.sub.6 H.sub.5 CH.sub.2                                                                       C.sub.6 H.sub.5 SCH.sub.2                                    (4-CH.sub.3 OC.sub.6 H.sub.5)CH.sub.2                                                          (naphth-2-yl)SCH.sub.2                                       __________________________________________________________________________

                                      TABLE 10G                                   __________________________________________________________________________     ##STR1514##                                                                  Entry                                                                             R.sup.2                                                                   __________________________________________________________________________    (CH.sub.3).sub.2 CHCH.sub.2                                                                    (4-FC.sub.6 H.sub.5)CH.sub.2                                 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                            (naphth-2-yl)CH.sub.2                                        CH.sub.3 SCH.sub.2 CH.sub.2                                                                    C.sub.6 H.sub.11 CH.sub.2                                    C.sub.6 H.sub.5 CH.sub.2                                                                       C.sub.6 H.sub.5 SCH.sub.2                                    (4-CH.sub.3 OC.sub.6 H.sub.5)CH.sub.2                                                          (naphth-2-yl)SCH.sub.2                                       __________________________________________________________________________

                                      TABLE 11A                                   __________________________________________________________________________     ##STR1515##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________    CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2       CH(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                  ##STR1516##                                                        __________________________________________________________________________

                                      TABLE 11B                                   __________________________________________________________________________     ##STR1517##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________    CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2       CH(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                      ##STR1518##                                                    __________________________________________________________________________

                                      TABLE 11C                                   __________________________________________________________________________     ##STR1519##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________    CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2       CH(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                      ##STR1520##                                                    __________________________________________________________________________

                                      TABLE 11D                                   __________________________________________________________________________     ##STR1521##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________    CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2       CH(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                      ##STR1522##                                                    __________________________________________________________________________

                                      TABLE 11E                                   __________________________________________________________________________     ##STR1523##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________    CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2       CH(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                      ##STR1524##                                                    __________________________________________________________________________

                                      TABLE 11F                                   __________________________________________________________________________     ##STR1525##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________    CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2       CH(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                         ##STR1526##                                                 __________________________________________________________________________

                                      TABLE 11G                                   __________________________________________________________________________     ##STR1527##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________    CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2       CH(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                         ##STR1528##                                                 __________________________________________________________________________

                                      TABLE 12A                                   __________________________________________________________________________     ##STR1529##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________     ##STR1530##                                                                   ##STR1531##                                                                  __________________________________________________________________________

                                      TABLE 12B                                   __________________________________________________________________________     ##STR1532##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________     ##STR1533##                                                                   ##STR1534##                                                                  __________________________________________________________________________

                                      TABLE 12C                                   __________________________________________________________________________     ##STR1535##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________     ##STR1536##                                                                   ##STR1537##                                                                  __________________________________________________________________________

                                      TABLE 12D                                   __________________________________________________________________________     ##STR1538##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________     ##STR1539##                                                                   ##STR1540##                                                                  __________________________________________________________________________

                                      TABLE 12E                                   __________________________________________________________________________     ##STR1541##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________     ##STR1542##                                                                   ##STR1543##                                                                  __________________________________________________________________________

                                      TABLE 12F                                   __________________________________________________________________________     ##STR1544##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________     ##STR1545##                                                                   ##STR1546##                                                                  __________________________________________________________________________

                                      TABLE 13A                                   __________________________________________________________________________     ##STR1547##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________     ##STR1548##                                                                             ##STR1549##                                                                               ##STR1550##                                                                               ##STR1551##                                 ##STR1552##                                                                             ##STR1553##                                                                               ##STR1554##                                                                               ##STR1555##                                 ##STR1556##                                                                             ##STR1557##                                                                               ##STR1558##                                                                               ##STR1559##                                 ##STR1560##                                                                             ##STR1561##                                                                               ##STR1562##                                                                               ##STR1563##                                 ##STR1564##                                                                             ##STR1565##                                                                                       ##STR1566##                                     ##STR1567##                                                                             ##STR1568##                                                                                       ##STR1569##                                     ##STR1570##                                                                                        ##STR1571##                                             __________________________________________________________________________

                                      TABLE 13B                                   __________________________________________________________________________     ##STR1572##                                                                  Entry                                                                             R.sup.3                                                                   __________________________________________________________________________     ##STR1573##                                                                             ##STR1574##                                                                               ##STR1575##                                                                               ##STR1576##                                 ##STR1577##                                                                             ##STR1578##                                                                               ##STR1579##                                                                               ##STR1580##                                 ##STR1581##                                                                             ##STR1582##                                                                               ##STR1583##                                                                               ##STR1584##                                 ##STR1585##                                                                             ##STR1586##                                                                               ##STR1587##                                                                               ##STR1588##                                 ##STR1589##                                                                             ##STR1590##                                                                                       ##STR1591##                                     ##STR1592##                                                                             ##STR1593##                                                                                       ##STR1594##                                     ##STR1595##                                                                                        ##STR1596##                                             __________________________________________________________________________

EXAMPLE 75

The compounds of the present invention are effective HIV proteaseinhibitors. Utilizing an enzyme assay as described below, the compoundsset forth in the examples herein disclosed inhibited the HIV enzyme. Thepreferred compounds of the present invention and their calculated IC₅₀(inhibiting concentration 50%, i.e., the concentration at which theinhibitor compound reduces enzyme activity by 50%) values are shown inTable 14. The enzyme method is described below. The substrate is2-Ile-Nle-Phe(p-NO₂)-Gln-ArgNH₂. The positive control is MVT-101(Miller, M. et al, Science, 246, 1149 (1989)! The assay conditions areas follows:

Assay buffer: 20 mM sodium phosphate, pH 6.4

20% glycerol

1 mM EDTA

1 mM DTT

0.1% CHAPS

The above described substrate is dissolved in DMSO, then diluted 10 foldin assay buffer. Final substrate concentration in the assay is 80 μM.HIV protease is diluted in the assay buffer to a final enzymeconcentration of 12.3 nanomolar, based on a molecular weight of 10,780.

The final concentration of DMSO is 14% and the final concentration ofglycerol is 18%. The test compound is dissolved in DMSO and diluted inDMSO to 10×the test concentration; 10 μl of the enzyme preparation isadded, the materials mixed and then the mixture is incubated at ambienttemperature for 15 minutes. The enzyme reaction is initiated by theaddition of 40 μl of substrate. The increase in fluorescence ismonitored at 4 time points (0, 8, 16 and 24 minutes) at ambienttemperature. Each assay is carried out in duplicate wells.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

EXAMPLE 76

The effectiveness of various compounds were determined in theabove-described enzyme assay and in a CEM cell assay.

The HIV inhibition assay method of acutely infected cells is anautomated tetrazolium based calorimetric assay essentially that reportedby Pauwles et al, J. Virol. Methods, 20, 309-321 (1988). Assays wereperformed in 96-well tissue culture plates. CEM cells, a CD4+ cell line,were grown in RPMI-1640 medium (Gibco) supplemented with a 10% fetalcalf serum and were then treated with polybrene (2 μug/ml). An 80 μlvolume of medium containing 1×104 cells was dispensed into each well ofthe tissue culture plate. To each well was added a 100 μl volume of testcompound dissolved in tissue culture medium (or medium without testcompound as a control) to achieve the desired final concentration andthe cells were incubated at 37° C. for 1 hour. A frozen culture of HIV-1was diluted in culture medium to a concentration of 5×10⁴ TCID₅₀ per ml(TCID₅₀ =the dose of virus that infects 50% of cells in tissue culture),and a 20 μl volume of the virus sample (containing 1000 TCID₅₀ of virus)was added to wells containing test compound and to wells containing onlymedium (infected control cells). Several wells received culture mediumwithout virus (uninfected control cells). Likewise, the intrinsictoxicity of the test compound was determined by adding medium withoutvirus to several wells containing test compound. In summary, the tissueculture plates contained the following experiments:

    ______________________________________                                        Cells              Drug   Virus                                               ______________________________________                                        1.      +              -      -                                               2.      +              +      -                                               3.      +              -      +                                               4.      +              +      +                                               ______________________________________                                    

In experiments 2 and 4 the final concentrations of test compounds were1, 10, 100 and 500 μg/ml. Either azidothymidine (AZT) or dideoxyinosine(ddI) was included as a positive drug control. Test compounds weredissolved in DMSO and diluted into tissue culture medium so that thefinal DMSO concentration did not exceed 1.5% in any case. DMSO was addedto all control wells at an appropriate concentration.

Following the addition of virus, cells were incubated at 37° C. in ahumidified, 5% CO₂ atmosphere for 7 days. Test compounds could be addedon days 0, 2 and 5 if desired. On day 7,post-infection, the cells ineach well were resuspended and a 100 μl sample of each cell suspensionwas removed for assay. A 20 μL volume of a 5 mg/ml solution of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) wasadded to each 100 μL cell suspension, and the cells were incubated for 4hours at 270° C. in a 5% CO₂ environment. During this incubation, MTT ismetabolically reduced by living cells resulting in the production in thecell of a colored formazan product. To each sample was added 100 μl of10% sodium dodecylsulfate in 0.01N HC1 to lyse the cells, and sampleswere incubated overnight. The absorbance at 590 nm was determined foreach sample using a Molecular Devices microplate reader. Absorbancevalues for each set of wells is compared to assess viral controlinfection, uninfected control cell response as well as test compound bycytotoxicity and antiviral efficacy.

                                      TABLE 14                                    __________________________________________________________________________                                                     IC.sub.50                                                                         EC.sub.50                Entry                                                                             Compound                                     (nM)                                                                              (nM)                     __________________________________________________________________________         ##STR1597##                                 3   6                        2                                                                                  ##STR1598##                                 10                           3                                                                                  ##STR1599##                                 4                            4                                                                                  ##STR1600##                                 4                            5                                                                                  ##STR1601##                                 10                           6                                                                                  ##STR1602##                                 24  123                      7                                                                                  ##STR1603##                                 7                            8                                                                                  ##STR1604##                                 27                           9                                                                                  ##STR1605##                                 4   39                       10                                                                                 ##STR1606##                                 16                           11                                                                                 ##STR1607##                                 22                           12                                                                                 ##STR1608##                                 7   187                      13                                                                                 ##STR1609##                                 5   71                       14                                                                                 ##STR1610##                                 4   81                       15                                                                                 ##STR1611##                                 3   47                       16                                                                                 ##STR1612##                                 4   21                       17                                                                                 ##STR1613##                                 4   160                      18                                                                                 ##STR1614##                                 6                            19                                                                                 ##STR1615##                                 11  174                      20                                                                                 ##STR1616##                                 4                            21                                                                                 ##STR1617##                                 9                            22                                                                                 ##STR1618##                                 63                           23                                                                                 ##STR1619##                                 12                           24                                                                                 ##STR1620##                                 25                           25                                                                                 ##STR1621##                                 6   43                       26                                                                                 ##STR1622##                                 16                           27                                                                                 ##STR1623##                                 75                           __________________________________________________________________________

The compounds of the present invention are effective antiviral compoundsand, in particular, are effective retroviral inhibitors as shown above.Thus, the subject compounds are effective HIV protease inhibitors. It iscontemplated that the subject compounds will also inhibit otherretroviruses such as other lentiviruses in particular other strains ofHIV, e.g. HIV-2, human T-cell leukemia virus, respiratory syncitialvirus, simia immunodeficiency virus, feline leukemia virus, felineimmuno-deficiency virus, hepadnavirus, cytomegalovirus and picornavirus.Thus, the subject compounds are effective in the treatment, proplylaxisof retroviral infections and/or the prevention of the spread ofretroviral infections.

The subject compounds are also effective in preventing the growth ofretroviruses in a solution. Both human and animal cell cultures, such asT-lymphocyte cultures, are utilized for a variety of well knownpurposes, such as research and diagnostic procedures includingcalibrators and controls. Prior to and during the growth and storage ofa cell culture, the subject compounds may be added to the cell culturemedium at an effective concentration to prevent the unexpected orundesired replication of a retrovirus that may inadvertently,unknowingly or knowingly be present in the cell culture. The virus maybe present originally in the cell culture, for example HIV is known tobe present in human T-lymphocytes long before it is detectable in blood,or through exposure to the virus. This use of the subject compoundsprevents the unknowing or inadvertent exposure of a potentially lethalretrovirus to a researcher or clinician.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or nonracemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, for example byformation of diastereoisomeric salts by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of Formula Iwith an optically pure acid in an activated form or an optically pureisocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomerically purecompound. The optically active compounds of Formula I can likewise beobtained by utilizing optically active starting materials. These isomersmay be in the form of a free acid, a free base, an ester or a salt.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Total daily dose administered to a host in single or divided doses maybe in amounts, for example, from 0.001 to 10 mg/kg body weight daily andmore usually 0.01 to 1 mg. Dosage unit compositions may contain suchamounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed may vary widely and thereforemay deviate from the preferred dosage regimen set forth above.

The compounds of the present invention may be administered orally,parenterally, by inhalation spray, rectally, or topically in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired. Topicaladministration may also involve the use of transdermal administrationsuch as transdermal patches or iontophoresis devices. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more immunomodulators, antiviral agents or other antiinfectiveagents. For example, the compounds of the invention can be administeredin combination with AZT, DDI, DDC or with glucosidase inhibitors, suchas N-butyl-l-deoxynojirimycin or prodrugs thereof, for the prophylaxisand/or treatment of AIDS. When administered as a combination, thetherapeutic agents can be formulated as separate compositions which aregiven at the same time or different times, or the therapeutic agents canbe given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. Compound represented by the formula: ##STR1624##or a pharmaceutically acceptable salt, prodrug or ester thereof, whereinn and t each independently represent 0, 1 or 2; W represents O or S;R¹represents hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl,cyanoalkyl, --CH₂ CONH₂, --CH₂ CH2CONH₂, --CH₂ S(O)₂ NH₂, --CH₂ SCH₃,--CH₂ S(O)CH₃ or --CH₂ S(O)₂ CH₃ radicals; R² represents alkyl, aralkyl,alkylthioalkyl, arylthioalkyl or cycloalkylalkyl radicals; R³ representsalkyl, cycloalkyl or cycloalkylalkyl radicals; R⁴ represents aryl,heteroaryl or heterocyclo radicals; or R⁴ represents a radical of theformula ##STR1625## wherein A and B each independently represent O, S,SO or SO₂ ; R⁶ represents deuterium, alkyl or halogen radicals; and R⁷represents hydrogen, deuterium, alkyl or halogen radicals; or R⁴represents a radical of the formula ##STR1626## wherein Z represents O,S or NH; and R⁹ represents a radical of formula ##STR1627## wherein Yrepresents O, S or NH; X represents a bond, O or NR²¹ ; R²⁰ representshydrogen, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl,heterocycloalkyl, aminoalkyl, N-mono-substituted or N,N-disubstitutedaminoalkyl wherein said substituents are alkyl, aralkyl, carboxyalkyl,alkoxycarbonylalkyl, cyanoalkyl or hydroxyalkyl radicals; or XR²⁰represents radicals of hydroxymethyl, aminomethyl, N-mono-substituted orN,N-disubstituted aminomethyl wherein said substituents are alkyl,aralkyl, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl or hydroxyalkylradicals; R²¹ represents hydrogen or alkyl radicals; or the radical offormula --NR²⁰ R²¹ represents a heterocyclo radical; and R²² representsalkyl or R²⁰ R²¹ N-alkyl radicals; and R⁵ represents heteroaryl orheterocyclo radicals each of which is coupled via a ring carbon atom, oralkyl radical substituted with R¹⁰, cycloalkylamino, aralkylamino,aminoalkoxycarbonyl, (alkylamino)alkoxycarbonyl,(dialkylamino)alkoxycarbonyl, (aminocarbonyl)(alkoxycarbonyl)methyl orbis(aminocarbonyl)methyl radicals or 1 or more radicals of amino,alkylamino or dialkylamino or 2 or more radicals of hydroxy or alkoxy;and R¹⁰ represents heteroaryl, heterocyclo, alkoxycarbonyl,arylcarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl orheterocyclocarbonyl radicals; or R¹⁰ represents R¹¹ R¹² N--C(O)--radical, wherein R¹¹ represents heteroaryl, heterocyclo, heteroaralkyl,heterocycloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,cycloalkylaminoalkyl, aralkylaminoalkyl or diaminoalkyl radicals; andR¹² represents hydrogen or alkyl radicals.
 2. Compound of claim 1 or apharmaceutically acceptable salt, prodrug or ester thereof, whereinR¹represents hydrogen, alkyl of 1-5 carbon atoms, alkenyl of 2-5 carbonatoms, alkynyl of 2-5 carbon atoms, hydroxyalkyl of 1-3 carbon atoms,alkoxyalkyl of 1-3 alkyl and 1-3 alkoxy carbon atoms, cyanoalkyl of 1-3alkyl carbon atoms, --CH₂ CONH₂, --CH₂ CH₂ CONH₂, --CH₂ S(O)₂ NH₂, --CH₂SCH₃, --CH₂ S(O)CH₃ or --CH₂ S(O)₂ CH₃ radicals; R² represents radicalsof alkyl of 1-5 carbon atoms, aralkyl of 1-3 alkyl carbon atoms,alkylthioalkyl of 1-3 alkyl carbon atoms, arylthioalkyl of 1-3 alkylcarbon atoms or cycloalkylalkyl of 1-3 alkyl carbon atoms and 3-6 ringmember carbon atoms; R³ represents radicals of alkyl of 1-5 carbonatoms, cycloalkyl of 5-8 ring members or cycloalkylmethyl of 3-6 ringmembers; R⁴ represents aryl, benzo fused 5 to 6 ring member heteroarylor benzo fused 5 to 6 ring member heterocyclo radicals; or R⁴ representsa radical of the formula ##STR1628## wherein A and B each independentlyrepresent O, S, SO or SO₂ ; R⁶ represents deuterium, alkyl of 1-5 carbonatoms, fluoro or chloro radicals; and R⁷ represents hydrogen, deuterium,alkyl of 1-3 carbon atoms, fluoro or chloro radicals; or R⁴ represents aradical of the formula ##STR1629## wherein Z represents O, S or NH; andR⁹ represents a radical of formula ##STR1630## wherein Y represents O, Sor NH;--X represents a bond, O or NR²¹ ; R²⁰ represents radicals ofhydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 2 to 5 carbon atoms,alkynyl of 2 to 5 carbon atoms, aralkyl of 1 to 5 alkyl carbon atoms,heteroaralkyl of 5 to 6 ring members and 1 to 5 alkyl carbon atoms,heterocycloalkyl of 5 to 6 ring members and 1 to 5 alkyl carbon atoms,aminoalkyl of 2 to 5 carbon atoms, N-mono-substituted orN,N-disubstituted aminoalkyl of 2 to 5 alkyl carbon atoms wherein saidsubstituents are radicals of alkyl of 1 to 3 carbon atoms, aralkyl of 1to 3 alkyl carbon atoms, carboxyalkyl of 1 to 5 carbon atoms,alkoxycarbonylalkyl of 1 to 5 alkyl carbon atoms, cyanoalkyl of 1 to 5carbon atoms or hydroxyalkyl of 2 to 5 carbon atoms; or XR²⁰ representsradicals of hydroxymethyl, aminomethyl, N-mono-substituted orN,N-disubstituted aminomethyl wherein said substituents are radicals ofalkyl of 1 to 3 carbon atoms, aralkyl of 1 to 3 alkyl carbon atoms,carboxyalkyl of 1 to 5 carbon atoms, alkoxycarbonylalkyl of 1 to 5 alkylcarbon atoms, cyanoalkyl of 1 to 5 carbon atoms or hydroxyalkyl of 2 to5 carbon atoms; R²¹ represents radicals of hydrogen or alkyl of 1 to 3carbon atoms; or the radical of formula --NR²⁰ R²¹ represents a 5 to 6ring member heterocyclo radical; and R²² represents alkyl or R²⁰ R²¹N-alkyl radicals wherein alkyl is 1 to 3 carbon atoms; and R⁵ represents5 to 6 ring member heteroaryl, 5 to 6 ring member heterocyclo, benzofused 5 to 6 ring member heteroaryl or benzo fused 5 to 6 ring memberheterocyclo radicals each of which is coupled via a ring carbon atom, oralkyl radical of 3-8 carbon atoms substituted with 2-5 radicals ofhydroxy or alkoxy of 1-3 carbon atoms or 2-3 radicals of amino,alkylamino of 1-3 carbon atoms or dialkylamino of 1-3 alkyl carboifatoms, or alkyl radical of 1-5 carbon atoms substituted with R¹⁰, oralkyl radical of 2-4 carbon atoms substituted with radicals of amino,alkylamino of 1-3 carbon atoms, dialkylamino of 1-3 alkyl carbon atoms,cycloalkylamino of 3-6 ring carbon atoms, aralkylamino of 1-3 alkylcarbon atoms, aminoalkoxycarbonyl of 2-5 alkoxy carbon atoms,(alkylamino)alkoxycarbonyl of 1-3 alkyl carbon atoms and 2-5 alkoxycarbon atoms, (dialkylamino)alkoxycarbonyl of 1-3 alkyl carbon atoms andof 2-5 alkoxy carbon atoms, (aminocarbonyl) (alkoxycarbonyl)methyl of1-3 alkoxy carbon atoms or bis(aminocarbonyl)methyl radicals; and R¹⁰represents alkoxycarbonyl of 1-5 alkoxy carbon atoms, arylcarbonyl, 3-6ring membered cycloalkylcarbonyl, benzo fused 3-6 ring memberedcycloalkylcarbonyl, 5 to 6 ring member heteroaryl, 5 to 6 ring memberheterocyclo, benzo fused 5 to 6 ring member heteroaryl, benzo fused 5 to6 ring member heterocyclo, 5 to 6 ring member heteroarylcarbonyl, 5 to 6ring member heterocyclocarbonyl, benzo fused 5 to 6 ring memberheteroarylcarbonyl or benzo fused 5 to 6 ring member heterocyclocarbonylradicals; or R¹⁰ represents R¹¹ R¹² N--C(O)-- radical, wherein R¹¹represents 5 to 6 ring member heteroaryl, 5 to 6 ring memberheterocyclo, benzo fused 5 to 6 ring member heteroaryl or benzo fused 5to 6 ring member heterocyclo radicals, or alkyl radical of 1-5 carbonatoms substituted with 5 to 6 ring member heteroaryl, 5 to 6 ring memberheterocyclo, benzo fused 5 to 6 ring member heteroaryl or benzo fused 5to 6 ring member heterocyclo radicals, or diaminoalkyl radical of 3-5carbon atoms, or alkyl radical of 2-4 carbon atoms substituted withradicals of amino, alkylamino of 1-3 carbon atoms, dialkylamino of 1-3alkyl carbon atoms, cycloalkylamino of 3-6 ring carbon atoms oraralkylamino of 1-3 alkyl carbon atoms; and R¹² represents radicals ofhydrogen or alkyl of 1-3 carbon atoms.
 3. Compound of claim 2 or apharmaceutically acceptable salt, prodrug or ester thereof, wherein nrepresents 1; t represents 1 or 2; W represents O;R¹ representshydrogen, alkyl of 1-3 carbon atoms, alkenyl of 2-3 carbon atoms,alkynyl of 2-3 carbon atoms or cyanomethyl radicals; R² representsradicals of alkyl of 3-5 carbon atoms, arylmethyl, alkylthioalkyl of 1-3alkyl carbon atoms, arylthiomethyl or cycloalkylmethyl of 5-6 ringmember carbon atoms; R⁴ represents aryl, benzo fused 5 to 6 ring memberheteroaryl or benzo fused 5 to 6 ring member heterocyclo radicals; or R⁴represents a radical of the formula ##STR1631## wherein A and B eachrepresent O; R⁶ represents deuterium, methyl, ethyl, propyl, isopropylor fluoro radicals; and R⁷ represents hydrogen, deuterium, methyl orfluoro radicals; or R⁴ represents a radical of the formula ##STR1632##wherein Z represents O, S or NH; and R⁹ represents a radical of formula##STR1633## wherein Y represents O, S or NH; X represents a bond, O orNR²¹ ; R²⁰ represents hydrogen, alkyl of 1 to 5 carbon atoms,phenylalkyl of 1 to 3 alkyl carbon atoms, heterocycloalkyl of 5 to 6ring members and 1 to 3 alkyl carbon atoms, or N-mono-substituted orN,N-disubstituted aminoalkyl of 2 to 3 carbon atoms wherein saidsubstituents are alkyl radicals of 1 to 3 carbon atoms; or XR²⁰represents radicals of hydroxymethyl, aminomethyl, N-mono-substituted orN,N-disubstituted aminomethyl wherein said substituents are radicals ofalkyl of 1 to 3 carbon atoms; R²¹ represents hydrogen or methylradicals; or the radical of formula --NR²⁰ R²¹ represents pyrrolidinyl,piperidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl,morpholinyl or thiomorpholinyl radicals; and R²² represents alkylradical of 1 to 3 carbon atoms; and R⁵ represents a 5 to 6 ring memberheteroaryl radical which is coupled via a ring carbon atom, or alkylradical of 1-5 carbon atoms substituted with R¹⁰, or alkyl radical of3-8 carbon atoms substituted with 2-5 hydroxy radicals; and R¹⁰represents alkoxycarbonyl of 1-4 alkoxy carbon atoms, arylcarbonyl, 5 to6 ring member heteroaryl, 5 to 6 ring member heterocyclo, benzo fused 5to 6 ring member heteroaryl, 5 to 6 ring member heteroarylcarbonyl or 5to 6 ring member heterocyclocarbonyl radicals; or R¹⁰ represents R₁₁ R¹²N--C(O)-- radical, wherein R₁₁ represents alkyl radical of 1-3 carbonatoms substituted with 5 to 6 ring member heteroaryl or 5 to 6 ringmember heterocyclo radicals; and R¹² represents hydrogen or methylradicals.
 4. Compound of claim 3 or a pharmaceutically acceptable salt,prodrug or ester thereof, whereinR¹ represents hydrogen, methyl, ethylor cyanomethyl radicals; R² represents isobutyl, n-butyl, CH3SCH₂ CH₂--, benzyl, phenylthiomethyl, (2-naphthylthio)methyl, 4-methoxyphenylmethyl, 4-hydroxyphenylmethyl, 4-fluorophenylmethyl orcyclohexylmethyl radicals; R³ represents propyl, isoamyl, isobutyl,butyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexyl or cycloheptylradicals; R²⁰ represents hydrogen, methyl, ethyl, propyl, isopropyl,isobutyl, benzyl, 2-(1-pyrrolidinyl)ethyl, 2-(1-piperidinyl)ethyl,2-(1-piperazinyl)ethyl, 2-(4-methylpiperazin-l-yl)ethyl,2-(4-morpholinyl)ethyl, 2-(4-thiomorpholinyl)ethyl or2-(N,N-dimethylamino)ethyl radicals; or XR²⁰ represents hydroxymethyl oraminomethyl radicals; R²¹ represents a hydrogen radical; and R¹⁰represents ethoxycarbonyl, tert-butoxycarbonyl, benzoyl, naphthoyl,aminophenylcarbonyl, amidinophenylcarbonyl, pyridylcarbonyl,thiazolylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl,pyrimidinylcarbonyl, pyrazinylcarbonyl, benzimidazolylcarbonyl,indolylcarbonyl, pyrrolylcarbonyl, quinolinylcarbonyl, pyrrolylcarbonyl,pyrrolidinylcarbonyl, 1-(benzyloxycarbonyl) pyrrolidinylcarbonyl,piperidinylcarbonyl, 1-(benzyloxycarbonyl)piperidinylcarbonyl,piperazinylcarbonyl, 4-methylpiperazinylcarbonyl,4-benzylpiperazinylcarbonyl, 4-(tert-butoxycarbonyl)piperazinylcarbonyl,morpholinylcarbonyl, thiomorpholinylcarbonyl,1,1-dioxothiomorpholinylcarbonyl, pyrrolidinyl, 1-oxopyrrolidin-1-yl,1-(benzyloxycarbonyl)pyrrolidinyl, piperidinyl, 1-oxopiperidin-1-yl,piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl,4-(tert-butoxycarbonyl)piperazinyl, morpholinyl, 4-oxomorpholin-4-yl,thiomorpholinyl, 1,l-dioxothiomorpholinyl,1,1,4-trioxothiomorpholin-4-yl, thiazolyl, oxazolyl, pyrrolyl, furyl,imidazolyl, pyrazolyl, isoxazolyl, thienyl, pyrimidinyl, pyrazinyl,pyridyl, quinolinyl, quinolonyl, N-methylquinolonyl, benzothiazolyl,benzoxazolyl, benzofuranyl, benzimidazolyl, indolyl,dihydroxytetrahydrofuran-5-yl, trihydroxytetrahydrofuran-5-yl,2-methoxydihydroxytetrahydrofuran-5-yl, trihydroxytetrahydrofuranyl,2-(hydroxymethyl)dihydroxytetrahydrofuran-5-yl,2-methoxytrihydroxytetrahydropyran-6-yl ortetrahydroxytetrahydropyran-6-yl radicals; or R¹⁰ represents R¹¹ R¹²N--C(O)-- radical, wherein R¹¹ represents 2-pyrrolidinylmethyl,2-(1-pyrrolidinyl)ethyl, 2-(1-oxopyrrolidin-1-yl)ethyl,2-(1-piperidinyl)ethyl, 2-(1-oxopiperidin-1-yl)ethyl,2-(4-morpholinyl)ethyl, 2-(4-oxomorpholin-4-yl)ethyl,2-(4-thiomorpholinyl)ethyl, 2-(1,1-dioxothiomorpholin-4-yl)ethyl or2-(1,1,4-trioxothiomorpholin-4-yl)ethyl radicals; and R¹² represents ahydrogen radical.
 5. Compound of claim 4 or a pharmaceuticallyacceptable salt, prodrug or ester thereof, whereinR¹ represents methylor ethyl radicals; R² represents benzyl, 4-fluorophenylmethyl orcyclohexylmethyl radicals; R⁴ represents phenyl, 2-naphthyl,4-methoxyphenyl, 4-hydroxyphenyl, 3,4-dimethoxyphenyl, 3-aminophenyl,4-aminophenyl, benzothiazol-5-yl, benzothiazol-6-yl,2-amino-benzothiazol-5-yl, 2-(methoxycarbonylamino) benzothiazol-5-yl,2-amino-benzothiazol-6-yl, 2-(methoxycarbonylamino) benzothiazol-6-yl,5-benzoxazolyl, 6-benzoxazolyl, 6-benzopyranyl,3,4-dihydrobenzopyran-6-yl, 7-benzopyranyl, 3,4-dihydrobenzopyran-7-yl,2,3-dihydrobenzofuran-5-yl, benzofuran-5-yl, 1,3-benzodioxol-5-yl,2-methyl-1,3-benzodioxol-5-yl, 2,2-dimethyl-1,3-benzodioxol-5-yl,2,2-dideutero-1,3-benzodioxol-5-yl, 2,2-difluoro-1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 5-benzimidazolyl,2-(methoxycarbonylamino)benzimidazol-5-yl, 6-quinolinyl, 7-quinolinyl,6-isoquinolinyl or 7-isoquinolinyl radicals; and R⁵ represents2-pyridyl, ethoxycarbonylpropyl, benzoylmethyl,morpholinylcarbonylmethyl,4-(tert-butoxycarbonyl)piperazinylcarbonylmethyl,piperazinylcarbonylmethyl,4-(tert-butoxycarbonyl)piperazinylcarbonylethyl,piperazinylcarbonylethyl, thiomorpholinylcarbonylmethyl,1,1-dioxothiomorpholinylcarbonylmethyl, imidazolylethyl,imidazolylcarbonylmethyl, pyrazolylethyl, thiazolylethyl,imidazolylmethyl, pyrazolylmethyl, thiazolylmethyl,benzimidazolylmethyl, pyridylethyl, pyridylcarbonylmethyl,pyrrolidinylmethyl, 1-(benzyloxycarbonyl)pyrrolidinylmethyl,5-methoxy-3,4-dihydroxy-tetrahydrofuranylmethyl, N-2-(4-oxomorpholin-4-yl)ethyl!aminocarbonylmethyl, N-2-(1-pyrrolidinyl)ethyl!aminocarbonylmethyl, N-2-(1-pyrrolidinyl)ethyl!aminocarbonylethyl, N-2-(1-oxopyrrolidin-1-yl)ethyl!aminocarbonylmethyl,2,2-bis(hydroxymethyl)ethyl, 2,2,2-tris(hydroxymethyl)ethyl, 2-(2-aminoethyl)aminocarbonyl!ethyl or 2-(2-(methylamino)ethyl)aminocarbonyl!ethyl radicals.
 6. Compound of claim5 or a pharmaceutically acceptable salt, prodrug or ester thereof,whereinR¹ represents a methyl radical; R² represents benzyl; R³represents isobutyl or cyclopentylmethyl radicals; R⁴ represents phenyl,2-naphthyl, 4-methoxyphenyl, 4-hydroxyphenyl, benzothiazol-5-yl,benzothiazol-6-yl, benzoxazol-5-yl, 2,3-dihydrobenzofuran-5-yl,benzofuran-5-yl, 1,3-benzodioxol-5-yl, 2-methyl-1,3-benzodioxol-5-yl,2,2-dimethyl-1,3-benzodioxol-5-yl, 2,2-dideutero-1,3-benzodioxol-5-yl,2,2-difluoro-1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2-(methoxycarbonylamino) benzothiazol-5-yl,2-(methoxycarbonylamino)benzothiazol-6-yl or2-(methoxycarbonylamino)benzimidazol-5-yl radicals; and R⁵ representsbenzoylmethyl, 4-(tert-butoxycarbonyl)piperazinylcarbonylmethyl,4-(tert-butoxycarbonyl)piperazinylcarbonylethyl,piperazinylcarbonylethyl, imidazolylethyl, pyrazolylethyl,thiazolylethyl, imidazolylmethyl, pyrazolylmethyl, thiazolylmethyl,pyridylethyl, pyridylcarbonylmethyl, pyrrolidinylmethyl or1-(benzyloxycarbonyl)pyrrolidinylmethyl radicals.
 7. Compound of claim 1wherein said pharmaceutically acceptable salt is hydrochloric acid salt,sulphuric acid salt, phosphoric acid salt, oxalic acid salt, maleic acidsalt, succinic acid salt, citric acid salt or methanesulfonic acid salt.8. Compound of claim 7 wherein said pharmaceutically acceptable,salt ishydrochloric acid salt, oxalic acid salt, citric acid salt ormethanesulfonic acid salt.
 9. Compound of claim 1 whichisN-(2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyridylcarbonylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-((2-pyridylcarbonylmethyl)sulfonyl!propanamide;N- 2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyridylcarbonylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyridylcarbonylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyridylcarbonylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyridylcarbonylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyridylcarbonylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-6-yl)sulfonyl)amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyridylcarbonylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyridylcarbonylmethyl)sulfonyl!ptopanamide; N- 2R-hydroxy-3-(2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyridylcarbonylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(4-pyridylcarbonylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(4-pyridylcarbonylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(4-pyridylcarbonylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(4-pyridylcarbonylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(4-pyridylcarbonylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyrazolylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyrazolylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyrazolylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyrazolylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(3-pyrazolylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(benzoylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3- (2-methylpropyl)(1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(benzoylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3- (2-methylpropyl)(benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(benzoylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3- (2-methylpropyl)(benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(benzoylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(benzoylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3- (2-methylpropyl)(1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(5-thiazolylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(5-thiazolylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(5-thiazolylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(5-thiazolylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(5-thiazolylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-2-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-2-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-2-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-2-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-2-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-3-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-3-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-3-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-3-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-3-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-4-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-4-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-4-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-4-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-pyrid-4-ylethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(1-(benzyloxycarbonyl)pyrrolidin-2S-ylmethyl)sulfonyl!propanamide; N-2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(1-(benzyloxycarbonyl)pyrrolidin-2S-ylmethyl)sulfonyl!propanamide; N-2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(1-(benzyloxycarbonyl)pyrrolidin-2S-ylmethyl)sulfonyl!propanamide; N-2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(1-(benzyloxycarbonyl)pyrrolidin-2S-ylmethyl)sulfonyl!propanamide; N-2R-hydroxy-3- (2-methylpropyl) (2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(1-(benzyloxycarbonyl)pyrrolidin-2S-ylmethyl)sulfonyl!propanamide; N-2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(1-piperazinylcarbonyl)ethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(1-piperazinylcarbonyl)ethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(1-piperazinylcarbonyl)ethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(l-piperazinylcarbonyl)ethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(1-piperazinylcarbonyl)ethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(2-aminoethylaminocarbonyl)ethyl)sulfonyl!propanamide; N-2R-hydroxy-3- (2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(2-aminoethylaminocarbonyl)ethyl)sulfonyl!propanamide; N-2R-hydroxy-3- (2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(2-aminoethylaminocarbonyl)ethyl)sulfonyl!propanamide; N-2R-hydroxy-3- (2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(2-aminoethylaminocarbonyl)ethyl)sulfonyl!propanamide; N-2R-hydroxy-3- (2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(2-(2-aminoethylaminocarbonyl)ethyl)sulfonyl!propanamide; N-2R-hydroxy-3- (2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-2-(hydroxymethyl)-3-hydroxypropyl!sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-2-(hydroxymethyl)-3-hydroxypropyl!sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-2-(hydroxymethyl)-3-hydroxypropyl!sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-2-(hydroxymethyl)-3-hydroxypropyl!sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1-(phenylmethyl)propyl!-2S-methyl-3-2-(hydroxymethyl)-3-hydroxypropyl!sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,3-benzodioxol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(pyrrolidin-2R-ylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (1,4-benzodioxan-6-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(pyrrolidin-2R-ylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-6-yl)sulfonyl!amino!-1-(phenylmethyl)propyl!-2S-methyl-3-(pyrrolidin-2R-ylmethyl)sulfonyl!propanamide; N- 2R-hydroxy-3-(2-methylpropyl) (benzothiazol-5-yl)sulfonyl!amino!-1S-(phenylmethyl)propyl!-2S-methyl-3-(pyrrolidin-2R-ylmethyl)sulfonyl!propanamide; or N- 2R-hydroxy-3-(2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl!amino!-1-(phenylmethyl)propyl!-2S-methyl-3-(pyrrolidin-2R-ylmethyl)sulfonyl!propanamide.
 10. Composition comprisinga compound of claim 1 and a pharmaceutically acceptable carrier. 11.Method of inhibiting a retroviral protease comprising administering aneffective amount of a compound of claim
 1. 12. Method of claim 11wherein the retroviral protease is HIV protease.
 13. Method of treatinga retroviral infection comprising administering an effective amount of acomposition of claim
 10. 14. Method of claim 13 wherein the retroviralinfection is HIV infection.
 15. Method of inhibiting replication of aretrovirus comprising administering an effective amount of a compound ofclaim
 1. 16. Method of claim 15 wherein the retrovirus is HIV. 17.Method of preventing replication of a retrovirus in vitro comprisingadministering an effective amount of a compound of claim
 1. 18. Methodof claim 17 wherein the retrovirus is HIV.
 19. Method of treating AIDScomprising administering an effective amount of a composition of claim10.
 20. Compound of claim 2 wherein R⁴ represents a benzo fused 5 to 6ring member heteroaryl; or a benzo fused 5 to 6 rinnmember heterocyclo;or R⁴ represents a radical of the formula: ##STR1634## wherein A and Beach independently represent O, S, SO or SO₂ ; R⁶ represents deuterium,an alkyl of 1-5 carbon atoms, fluoro or chloro;R⁷ represents hydrogen,deuterium, an alkyl of 1-3 carbon atoms, fluoro or chloro; or R⁴represents a radical of the formula ##STR1635## wherein Z represents O,S or NH; and R⁹ represents a radical of formula ##STR1636## wherein Yrepresents O, S or NH; X represents a bond, O or NR² ; R²⁰ representshydrogen, an alkyl of 1 to 5 carbon atoms, an alkenyl of 2 to 5 carbonatoms, an alkynyl of 2 to 5 carbon atoms, an aralkyl of 1 to 5 alkylcarbon atoms, a heteroaralkyl of 5 to 6 ring members and 1 to 5 alkylcarbon atoms, a heterocycloalkyl of 5 to 6 ring members and 1 to 5 alkylcarbon atoms, an aminoalkyl of 2 to 5 carbon atoms, anN-mono-substituted or N, N-disubstituted aminoalkyl of 2 to 5 alkylcarbon atoms wherein said substituents are selected from radicals of analkyl of 1 to 3 carbon atoms, an aralkyl of 1 to 3 alkyl carbon atoms, acarboxyalkyl of 1 to 5 carbon atoms, an alkoxycarbonylalkyl of 1 to 5alkyl carbon atoms, a cyanoalkyl of 1 to 5 carbon atoms and ahydroxyalkyl of 2 to 5 carbon atoms; or XR20 represents hydroxymethyl,aminomethyl, N-mono-substituted or N, N-disubstituted aminomethylwherein said substituents are an alkyl of 1 to 3 carbon atoms, anaralkyl of 1 to 3 alkyl carbon atoms, a carboxyalkyl of 1 to 5 carbonatoms, an alkoxycarbonlalkyl of 1 to 5 alkyl carbon atoms, a cyanoalkylof 1 to 5 alkyl atoms or a hydroxyalkyl of 2 to 5 carbon atoms; R²¹represents hydrogen; or an alkyl of 1 to 3 carbon atoms; or the radicalof formula --NR²⁰ R²¹ represents a 5 to 6 ring member heterocycloradical; and R>represents an alkyl of 1 to 3 carbon atoms or a R²⁰ R²¹N--alkyl of 1 to 3 alkyl carbon atoms.
 21. Compound of claim 3 whereinR⁴ represents a benzo fused 5 to 6 ring member heteroaryl; or a benzofused 5 to 6 ring member heterocyclo; or R⁴ represents a radical of theformula: ##STR1637## wherein A and B each represent O; R⁶ representsdeuterium, methyl, ethyl, propyl, isopropyl or fluoro;R⁷ representshydrogen, deuterium, methyl, or fluoro; or R⁴ represents a radical ofthe formula ##STR1638## wherein Z represents O, S or NH; and R⁹represents a radical of formula ##STR1639## wherein Y represents O, S orNH; X represents a bond, O or NR²¹ ; R²⁰ represents hydrogen, an alkylof 1 to 5 carbon atoms, a phenylalkyl of 1 to 3 alkyl carbon atoms, aheterocycloalkyl of 5 to 6 ring members and 1 to 3 alkyl carbon atoms,or an N-mono-substituted or N, N-disubstituted aminoalkyl of 2 to3carbon atoms wherein said substituents are alkyl radicals of 1 to 3carbon atoms; or XR²⁰ represents radicals of hydroxymethyl, aminomethyl,N-mono-substituted or N,N-disubstitutedr aminomethyl wherein saidsubstituents are selected from radicals of an alkyl of 1 to 3 carbonatoms, R²¹ represents hydrogen; or methyl; or the radical of formula--NR²⁰ R²¹ represents pyrrolidinyl piperidinyl, piperazinyl,4-methylpiperazinyl, 4-benzylpiperazinyl, morpholinyl orthiomorpholinyl; and R²² represents an alkyl of 1 to 3 carbon atoms. 22.Compound of claim 4 wherein R⁴ represents a benzo fused 5 to 6 ringmember heteroaryl; or a benzo fused 5 to 6 ring member heterocyclo; orR⁴ represents a radical of the formula: ##STR1640## wherein A and B eachrepresent O; ⁶ represents deuterium, methyl, ethyl, propyl, isopropyl orfluoro;R⁷ represents hydrogen, deuterium, methyl, or fluoro; or R⁴represents a radical of the formula ##STR1641## wherein Z represents O,or NH; and R⁹ represents a radical of formula ##STR1642## wherein Yrepresents O, S or NH; X represents a bond, O or NR²¹ ; R²⁰ representshydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl,2-(1-pyrrolidinyl)ethyl, 2-(1-piperidinyl)ethyl, 2-(1-piperazinyl)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 2-(4-morpholinvl)ethyl,2-(4-thiomorpholinvyl)ethyl or 2-(N,N-dimethylamino)ethyl or XR²⁰represents hydroxmethyl or aminomethyl radicals; and R²¹ representshydrogen.